Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000441.1(SLC26A4):c.1229C>T (p.Thr410Met)

CA261403

43498 (ClinVar)

Gene: SLC26A4
Condition: Pendred syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 034f39b8-0469-47c1-b9ac-930299df3dc7

HGVS expressions

NM_000441.1:c.1229C>T
NM_000441.1(SLC26A4):c.1229C>T (p.Thr410Met)
NC_000007.14:g.107690203C>T
CM000669.2:g.107690203C>T
NC_000007.13:g.107330648C>T
CM000669.1:g.107330648C>T
NC_000007.12:g.107117884C>T
NG_008489.1:g.34569C>T
ENST00000265715.7:c.1229C>T

Pathogenic

Met criteria codes 6
PM2_Supporting PM3_Very Strong PP3 PP4 PS3_Supporting PP1_Strong
Not Met criteria codes 17
BS1 BS4 BS2 BP7 BP5 BP4 BP3 BP2 PM6 PM4 PM1 PM5 PS1 PS2 PS4 BA1 PVS1

Evidence Links 24

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VeryStrong; PMID: 25372295, 23638949, 25468468, 24338212, 25394566, 19786220, 19017801, 27541434, 21366435, 17309986, 24007330, 24224479, 21961810, 2844304, 19509082, 15811013). The p.Thr410Met variant in SLC26A4 has been reported to segregate in an autosomal recessive pattern with hearing loss in at least 7 family members (PP1_Strong; PMID: 19017801, 9618167, 15811013). Computational prediction tools and conservation analysis suggest that the p.Thr410Met variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA or Mondini malformation (PP4; PMID: 15355436, 15811013). The allele frequency of the p.Thr410Met variant in the SLC26A4 gene is 0.062% (19/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PP1_S, PP3, PS3_P, PM2_P, PP4.
Met criteria codes
PM2_Supporting
19/30782 0.06172% Just under the cutoff for PM2_P (0.0007). , no homzygotes reported in gnomAD.
PM3_Very Strong
This variant meets the criteria for PM3_VS
Identified the varaint in trans with a p.Gly209Val variant (Path by 5 submitters in ClinVar) in one patient and a p.Glu29Gln variant in another patient (P by LMM LP/P by 2 other labs in ClinVar). PubMed:25394566
This study identified 2 cases who were compound heterozygous for this variant out of 9317 Southern Chinese newborns. These individuals were part of 34 other indiivudals who had causal variants identiied in the paper but (most) passed newborn screening. One indiviudal had the p.Val659Leu variant in trans, while the other individual had the c.912-2A>G variant. Both are pathogenic.These two indiviudals did NOT pass the newborn screening and were foudn to have severe/moderate hearing loss based on the referral. Most of the individuals that passed were m.1555A>G PubMed:27541434
Identified a case with EVA and a compound het genotype: G209V/T410M. The G209V variant is a pathogenic variant in ClinVar by 5 submitters. This would count as 1.0 points for PM3 PubMed:17309986
Identified 2 compound het individuals with p.H723R and p.V659L as the variants in trans with p.T410M PubMed:23638949
This study identified a compound heterozygous case with thyroid dysgenesis and p.T310M/p.V678V variants in SLC26A4. The p.V678V variant occurs in the last bp of the last codon in exon 17/21. This varaint is a VUS (already maxed to PM3_VS). PubMed:28444304
This study identified 3 French probands with Pendred syndrome and the variant. 2 compound het, both with p.Y530H in trans, and one homozygous p.T410M. p.Y530H is a pathogenic/LPvaraint in ClinVar (LMM: path). Therefore this would count as 2.5 points for PM3 counts. PubMed:15355436
Seqeunced 1057 Chinese HL patients. Identified 27 patients with the c.919-2A>G variant in trans with the p.T410M. 8 patients with the genotype: c.2168A.G(p.H723R) c.1229C.T(pT410M). 4 homozygotes. 3 patients with the genotype p.V659L/p.T410M. Identified 2 cases of the varaint in trans with the p.N392Y variant. Identified 2 patients with the c.1687_1692insA variant in trans with the p.T140M variant. One case in trans with the p.T94I variant. One case in trans with the p.V650D variant. One case in trans with the c.1693insA variant. One patient with the p.S448X variant in trans. One patient with the IVS19+2T>A variant in trans. There were many more variants in trans and 4 cases with wt in trans, but since the PM3 points are maxed, they will not be noted here. PubMed:25372295
SLC26A4 p.Thr410Met homozygous mutation in a patient with a cystic cochlea and an enlarged vestibular aqueduct showing characteristic features of incomplete partition type I and II PubMed:25468468
2 compound het individuals from the same family with the p.H723R/p.T410M genotype and hearing loss. One had stable HL and the other had fluctuating hearing loss. PubMed:24338212
Family from a small village but not known to be consanguineous had 4 affected homozygotes of the T410M mutation but also had a compound heterozygote with the D724G variant. This variant was submitted to ClinVar as pathogenic by the LMM (only ClinVar submission). Therefore this family would provide 1.0 points for PM3 as the compound het case would be the only one scored. PubMed:15811013
This study identified another indiviudal with the p.T410M/p.D724G genotype. This individual had severe/profound hearing loss, Mondini malformation. This individual was actually a proband for family S154 which had 4 other individuals who were homozygous for the p.T410M varaint and had profound HL and EVA. PubMed:19017801
From a cohort of 51 hearing impaired individuals from 46 families, identified one homozygous individual. PubMed:21366435
Identified pT410M in trans with p.N392Y in a Chinese EVA patient. This variant has been identified as pathogenic by one submitter in ClinVar (Dividsion of Hearing and Balance Research, NHO Tokyo). PubMed:19786220
This paper also identified a case with compound heterozygous mutations p.Thr410Met and p.Tyr530His in SLC26A4. The patient had cochlear dysplaisa, EVA, no Goiter, congenital hypothyroidism, and was an 8 year old male. The p.Tyr530His variant is considered pathogenic. PubMed:24224479
This study investigated 144 patients with SNHL adn temporal bone malformations and found that 6 patients had the p.T410M variant. There was one comp. het. indiviudal with a p.A360V variant in trans, 4 compound het individuals with the c.919-2 A>G splice variant, 1 individual with the p.SF532, 545* variant, and one indivudal with the c.1343C>A p.S448X variant. PubMed:21961810
This study identified a deaf Korean proband who was heterozygous for the variant. No other allele was reported. This cannot be added as support for PM3 but may be useful information. PubMed:12676893
Identified patients with p.H723R/p.T410M genotype and found that they had better residual hearing thatn those with homozygous p.H723R genotype. THere is little detail about the patients themselves and therefore it is unclear how many cases they had, but there were 4 alleles of the p.T410M variant PubMed:24007330
This study identified 2 patients with the p.T410M variant and NSHL w/a temporal bone abnormality. One individual was homozygous and the other had a c.1199insT variant (p.Cys400TrpfsX68) which is a convincing LOF variant. This paper would also provide 1.5 PM3 points. PubMed:19509082
PP3
REVEL score of 0.907 meets the 0.7 threshold.
PP4
Pendred syndrome and the inner ear malformations associated with the disorder are considered supporting evidence for pathogenicity of variants in SLC26A4.
This study also describes PS families with the variant. PubMed:15355436
4 homozygous occurances have EVA, and the compound heterozygous individual has a Mondini malformation and incudomallel fusion. PubMed:15811013
PS3_Supporting
As a membrane protein, SLC26A4's anion exchange function is important to its utility in the cell and likely is involved in preventing the malformations associated with Pendred syndrome. RS: I would be cautious and not apply PS3, because the findings are not clear.
Studied the functional effects of the T410M variant and found that transfection in HEK293 cells prevented the varaint from reaching the cell membrane and hypothesized thtat the variant was causing misfolding/ multiprocessing in the Gogli. Of note: this result was NOT replicated in Lee et al. 2014 PubMed:11932316
This study analyzed the surface expression and anion exchange activity of mutant pendrin and found that p.T410M as well as p.H723R mutant pendrin actually was expressed at the plasma membrane after transfection in HEK293 cells despite previous studies showing that the variants prevented localization to the plasma membrane from protein folding defects. The study also foudn that the anion exchange activiy of pendrin localized to the plasma membrane of transfected cells and p.T410M plasmids had signfiicantly higher anion exchange activiites than the cells with p.H723R. However, both had lower activity than the wild type. PubMed:24007330
PP1_Strong
The family from Arellano 2005 alone has 4 affected segregations and 3 unaffected segregations if you count the ather in gen I as an obligate carrier of teh p.T410Met variant. Additionally, the family in Pera et al. may have 3 affected segregations as well.
This study identified the T410M variant in a consanguineous Pakistani family, but did not indicate any further information. PubMed:9618167
Segregation in a family from a small village (not thought to be consanguineous) resulted in 5 total affecteds and 4 total unaffecteds, though the mother I.1 and the father II.2 shouldn't be counted as unaffecteds because the genotype of their parents is unknown. Therefore 5 affected, 3 unaffected leads to a LOD for this family of 3.39 which constitutes a PP1_Strong modification. Additionally, one individual was a compound heterozygote with a the D724G missense variant inherited from the mother. PubMed:15811013
Identified a family with a proband who had a p.D724G varaint in trans with the p.T410M variant, but had 4 affected relatives who were homozygous for the p.T410M variant. PubMed:19017801
Not Met criteria codes
BS1
19/30782 0.06172% Just under the cutoff for PM2_P (0.0007). , no homzygotes reported in gnomAD.
BS4
This study identified the T410M variant in a consanguineous Pakistani family, but did not indicate any further information. PubMed:9618167
Segregation in a family from a small village (not thought to be consanguineous) resulted in 5 total affecteds and 4 total unaffecteds, though the mother I.1 and the father II.2 shouldn't be counted as unaffecteds because the genotype of their parents is unknown. Therefore 5 affected, 3 unaffected leads to a LOD for this family of 3.39 which constitutes a PP1_Strong modification. Additionally, one individual was a compound heterozygote with a the D724G missense variant inherited from the mother. PubMed:15811013
Identified a family with a proband who had a p.D724G varaint in trans with the p.T410M variant, but had 4 affected relatives who were homozygous for the p.T410M variant. PubMed:19017801
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
compound het GJB2 and SLC26A4 mutations in this case, but nto allowed to use for AR.
Mutational analysis identified compound heterozygosity for the c.257C>G (p.T86R) and c.299-300delAT mutations in GJB2, and the c.1229C>T (p.T410M) and c.1079C>T (p.A360V) mutations in SLC26A4 in the proband. His father was confirmed to carry the c.299-300delAT mutation in GJB2 and p.A360V in SLC26A4, and his mother carried the p.T86R mutation in GJB2 and p.T410M in SLC26A4. The results suggested that his parents were both coincident GJB2 and SLC26A4 mutation carriers, but with normal hearing. PubMed:23266159
BP4
REVEL score of 0.907 meets the 0.7 threshold.
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
Identified the varaint in trans with a p.Gly209Val variant (Path by 5 submitters in ClinVar) in one patient and a p.Glu29Gln variant in another patient (P by LMM LP/P by 2 other labs in ClinVar). PubMed:25394566
This study identified 2 cases who were compound heterozygous for this variant out of 9317 Southern Chinese newborns. These individuals were part of 34 other indiivudals who had causal variants identiied in the paper but (most) passed newborn screening. One indiviudal had the p.Val659Leu variant in trans, while the other individual had the c.912-2A>G variant. Both are pathogenic.These two indiviudals did NOT pass the newborn screening and were foudn to have severe/moderate hearing loss based on the referral. Most of the individuals that passed were m.1555A>G PubMed:27541434
Identified a case with EVA and a compound het genotype: G209V/T410M. The G209V variant is a pathogenic variant in ClinVar by 5 submitters. This would count as 1.0 points for PM3 PubMed:17309986
Identified 2 compound het individuals with p.H723R and p.V659L as the variants in trans with p.T410M PubMed:23638949
This study identified a compound heterozygous case with thyroid dysgenesis and p.T310M/p.V678V variants in SLC26A4. The p.V678V variant occurs in the last bp of the last codon in exon 17/21. This varaint is a VUS (already maxed to PM3_VS). PubMed:28444304
This study identified 3 French probands with Pendred syndrome and the variant. 2 compound het, both with p.Y530H in trans, and one homozygous p.T410M. p.Y530H is a pathogenic/LPvaraint in ClinVar (LMM: path). Therefore this would count as 2.5 points for PM3 counts. PubMed:15355436
Seqeunced 1057 Chinese HL patients. Identified 27 patients with the c.919-2A>G variant in trans with the p.T410M. 8 patients with the genotype: c.2168A.G(p.H723R) c.1229C.T(pT410M). 4 homozygotes. 3 patients with the genotype p.V659L/p.T410M. Identified 2 cases of the varaint in trans with the p.N392Y variant. Identified 2 patients with the c.1687_1692insA variant in trans with the p.T140M variant. One case in trans with the p.T94I variant. One case in trans with the p.V650D variant. One case in trans with the c.1693insA variant. One patient with the p.S448X variant in trans. One patient with the IVS19+2T>A variant in trans. There were many more variants in trans and 4 cases with wt in trans, but since the PM3 points are maxed, they will not be noted here. PubMed:25372295
SLC26A4 p.Thr410Met homozygous mutation in a patient with a cystic cochlea and an enlarged vestibular aqueduct showing characteristic features of incomplete partition type I and II PubMed:25468468
2 compound het individuals from the same family with the p.H723R/p.T410M genotype and hearing loss. One had stable HL and the other had fluctuating hearing loss. PubMed:24338212
Family from a small village but not known to be consanguineous had 4 affected homozygotes of the T410M mutation but also had a compound heterozygote with the D724G variant. This variant was submitted to ClinVar as pathogenic by the LMM (only ClinVar submission). Therefore this family would provide 1.0 points for PM3 as the compound het case would be the only one scored. PubMed:15811013
This study identified another indiviudal with the p.T410M/p.D724G genotype. This individual had severe/profound hearing loss, Mondini malformation. This individual was actually a proband for family S154 which had 4 other individuals who were homozygous for the p.T410M varaint and had profound HL and EVA. PubMed:19017801
From a cohort of 51 hearing impaired individuals from 46 families, identified one homozygous individual. PubMed:21366435
Identified pT410M in trans with p.N392Y in a Chinese EVA patient. This variant has been identified as pathogenic by one submitter in ClinVar (Dividsion of Hearing and Balance Research, NHO Tokyo). PubMed:19786220
This paper also identified a case with compound heterozygous mutations p.Thr410Met and p.Tyr530His in SLC26A4. The patient had cochlear dysplaisa, EVA, no Goiter, congenital hypothyroidism, and was an 8 year old male. The p.Tyr530His variant is considered pathogenic. PubMed:24224479
This study investigated 144 patients with SNHL adn temporal bone malformations and found that 6 patients had the p.T410M variant. There was one comp. het. indiviudal with a p.A360V variant in trans, 4 compound het individuals with the c.919-2 A>G splice variant, 1 individual with the p.SF532, 545* variant, and one indivudal with the c.1343C>A p.S448X variant. PubMed:21961810
This study identified a deaf Korean proband who was heterozygous for the variant. No other allele was reported. This cannot be added as support for PM3 but may be useful information. PubMed:12676893
Identified patients with p.H723R/p.T410M genotype and found that they had better residual hearing thatn those with homozygous p.H723R genotype. THere is little detail about the patients themselves and therefore it is unclear how many cases they had, but there were 4 alleles of the p.T410M variant PubMed:24007330
This study identified 2 patients with the p.T410M variant and NSHL w/a temporal bone abnormality. One individual was homozygous and the other had a c.1199insT variant (p.Cys400TrpfsX68) which is a convincing LOF variant. This paper would also provide 1.5 PM3 points. PubMed:19509082
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No other missense variants found at this codon in LMM database, ClinVar, or HGMD, but gnomAD does have p.Thr410Ala and p.Thr410Arg variants in 1 allele each.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Though there were proband counts indicating that this variant may affect the protein in an AD manner, this is not the established mechanism for Pendred syndrome and SLC26A4.
This publication identiifed the variant in a patient from a hearing loss cohort and said they found it affecting the individual in an AD manner. PubMed:26763877
This study found one patient with the varaint who had EVA/MD but did not identifiy further information about the case. PubMed:15905611
This article does not perform a useable case control study. It does, however provide 4/60 alleles from individuals with inner ear malformations associated with hearing loss. There is no further information on the phase of the variants or the patient's themselves. This cannot be used as evidence, but may be factored into a statistical analysis. PubMed:22412181
BA1
19/30782 0.06172% Just under the cutoff for PM2_P (0.0007). , no homzygotes reported in gnomAD.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2018-09-17
Published on: 2019-07-17
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