The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries.
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Variant: NM_000441.1(SLC26A4):c.349C>T
- Curation Version - 1.0
- Curation History
- JSON LD for Version 1.0
CA132727
43555 (ClinVar)
Gene: SLC26A4
Condition: Pendred syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 67c2f97e-385f-494a-b06e-701135ace536
Approved on: 2018-09-26
Published on: 2019-07-17
HGVS expressions
NM_000441.1:c.349C>T
NM_000441.1(SLC26A4):c.349C>T
NC_000007.14:g.107672182C>T
CM000669.2:g.107672182C>T
NC_000007.13:g.107312627C>T
CM000669.1:g.107312627C>T
NC_000007.12:g.107099863C>T
NG_008489.1:g.16548C>T
ENST00000644269.2:c.349C>T
ENST00000265715.7:c.349C>T
ENST00000440056.1:c.349C>T
NM_000441.2:c.349C>T
More
Likely Pathogenic
Met criteria codes 6
PM3_Very Strong
BS1
PP1_Strong
BS3_Supporting
PP3
PP4
Not Met criteria codes 20
PVS1
PM6
PM2
PM1
PM5
PM4
BA1
BS4
BS2
BP5
BP7
BP4
BP3
BP1
BP2
PS1
PS2
PS3
PS4
PP2
Evidence Links 5
Expert Panel
Evidence submitted by expert panel
Hearing Loss VCEP
This variant has been detected in 4 patients with hearing loss in trans with p.Val570Ile, p.Thr416Pro, c.-4+1>C and p.Thr193Ile (PM3_VeryStrong; Partners LMM unpublished internal data, PMID: 26969326, Karen Avraham Lab internal data SCV000282015.2). Of note, the variant has also been observed in heterozygosity in two individuals with enlarged vestibular aqueduct, in which a second allele was not identified (PMID: 16570074, 10700480), however, this is not uncommon for patients with hearing loss due to SLC26A4. The p.Leu117Phe variant in SLC26A4 has been reported to segregate with hearing loss in at least 5 affected and 4 unaffected family members, across 2 Ashkenazi Jewish families with hearing loss (PP1_Strong; Karen Avraham Lab internal data SCV000282016.1, SCV000282017.1). At least four probands with the p.Leu117Phe variant in compound heterozygosity with a second pathogenic or suspected-pathogenic SLC26A4 variant displayed features of EVA (PP4; Partners LMM unpublished internal data, PMID: 26969326). Computational prediction analysis using REVEL suggests that the variant may impact the protein (PP3). A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID: 27771369, 11932316), however, the functional may not assess all ion transport functions of the protein and/or ensure that the assay reflects the true biological environment and therefore the ClinGen Hearing Loss Expert Panel (HL EP) chose not to consider this evidence fully in conflict with the pathogenic evidence. The filtering allele frequency of the p.Leu117Phe variant in the SLC26A4 gene is 0.4% for Ashkenazi Jewish chromosomes by the Genome Aggregation Database (52/10150 with 95% CI) based on thresholds defined by the ClinGen HL EP for autosomal recessive Pendred syndrome variants (BS1). However, given the lack of understanding of Pendred syndrome prevalence in the Ashkenazi Jewish population and the finding that a study of ~10,000 Jewish hearing individuals detected no homozygotes (Karen Avraham Lab internal data SCV000282015.2) this allele frequency was not considered strong enough conflicting evidence to counter the pathogenic evidence. In summary, this variant has been classified as likely pathogenic for autosomal recessive Pendred syndrome based on the full set of evidence described above. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PP1_Strong, PP4, PP3, BS1, BS3_Supporting.
Met criteria codes
PM3_Very Strong
There is one LMM case w/ EVA and HL that is compound heterozygous for this variant and the p.Thr416Pro SLC26A4 variant which is classified as Pathogenic by LMM (1 pt). There are also 2 probands at the LMM of a compound het with a VUS-5 p.Val570Ile variant one with EVA, both with HL (0.5 pts x 2). There is another LMM compound het with EVA with a p.Thr508Ala variant which is also VUS-5 (0.5 pts). There are also 3 heterozygotes for this variant reported all with EVA (0.25 x 3). (1 LMM case, Reardon 2000, Albert 2006). Sloan Heggen reports the variant in trans with a VUS splice variant (0 pts). In ClinVar, there is also a case reported by K.A. in trans with a p.Thr193Ile variant which is Pathogenic (1 pt).
4.25 pts = PM3_VS
Should the HL EP specify that in trans with VUS 5 is 0.5 pts? Also can we count SLC26A4 het's as 0.25 with the 1 point limit?
1119 patients with hearing loss tested. Found one compound heterozygote with this variant in trans with a splicing c.-4+1G>C variant with severe to profound hearing loss, but not noted if they tested temporal bone imaging. Shouldn't be used for PM3, as the splice variant is VUS.
PubMed:26969326
57 EVA patients screened for SLC26A4. Found in one patinet with HL and EVA but a normal perchlorate test. Did not note a second variant. Variant was absent from 100 control chromosomes-no family/race info
PubMed:10700480
109 patients from 100 families with nonsyndromic hearing loss and EVA. 50 control individuals, study in France. The variant was seen in one affected patient without a second variant.
PubMed:16570074
BS1
Despite having a filtered allele frequency in Ashkenazi Jewish population in gnomAD of 0.4%, this variant is on the ClinGen Hearing Loss Expert Panel's exclusion list for BS1.
PP1_Strong
This variant segregates with disease in at least 3 affected and 4 unaffected individuals from Karen Avraham's lab. They also report an additional 5 Ashkenzazi families with segregation of this variant and HL.
RS10/9/18 Update: Variant seen in 7 affected homozygous individuals and 3 affected heterozygous individuals, only one of whom has a second variant identified in trans. At least 4 homozygous segregations meets criteria for strong.
BS3_Supporting
The variant did not have an impact on the localization, or the iodide efflux capacity, however not all ion transport functions of the proteins were assessed.
Noted variant lacking experimentally validated functional information. Conserved and gives NeEMO stability 1.37. Predicted Benign in silico. predicted molecular effect maintenance of hydrophobicity.
PubMed:27771369
This study investigated the impact of 9 different SLC26A4 variants on protein function. They found that the L117F variant showed a cell membrane protein distribution similar to that of the wild type protein and exhibited a rate of iodide efflux statistically similar to that of the WT. this study actually questioned as to whether there was an alternate cause in the case from the study. This study would support a benign impact of the variant, however it is also important to note that this study didn't investigate all ion transport functions.
PubMed:11932316
PP3
Meets REVEL 0.7 cutoff for pathogenicity.
PP4
This variant has been identified in patients with EVA, which is a phenotype that was deemed to be highly specific for SLC26A4 by the ClinGen Hearing Loss Expert Panel.
Patient with EVA and variant
PubMed:10700480
Patient with EVA and variant.
PubMed:16570074
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
Despite having a filtered allele frequency in Ashkenazi Jewish population in gnomAD of 0.4%, this variant is on the ClinGen Hearing Loss Expert Panel's exclusion list for BS1.
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
There is a reported genotype of a compund het case with the c.578C>T variant that was interpreted as pathogenic by a zero star submitter, but there are no other missense variants reported at this codon in ClinVar.
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Despite having a filtered allele frequency in Ashkenazi Jewish population in gnomAD of 0.4%, this variant is on the ClinGen Hearing Loss Expert Panel's exclusion list for BS1.
BS4
There are 2 family members in LMM's internal data who are unaffected but are heterozygous for the p.Leu117Phe variant. However, they don't have the other variant that is in trans in the affected individual.
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
While this variant has been suspected to have an alternate cause in patients due to its lack of known functional implications and the patient in Taylor et al. 2002's lack of thyroid dysfunction at age 18 yr, but a second variant was not identified.
In an LMM case, there was a patient without EVA that had this variant as well as a heterozygous pathogenic c.459delC KCNQ4 variant which is known to cause AD HL. Therefore, BP5 could be applied here.
RS 9/18/18 After review, this criteria has been determined not met.
Mutant performed as wild type pendrin on iodide efflux assay and also showed normal localization. Unclear of the variant impacts another ion transport function of the protein as OH, HCO3, Cl were not assessed.
PubMed:11932316
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
Meets REVEL 0.7 cutoff for pathogenicity.
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
z=-3.23
BP2
1119 patients with hearing loss tested. Found one compound heterozygote with this variant in trans with a splicing c.-4+1G>C variant with severe to profound hearing loss, but not noted if they tested temporal bone imaging. Shouldn't be used for PM3, as the splice variant is VUS.
PubMed:26969326
57 EVA patients screened for SLC26A4. Found in one patinet with HL and EVA but a normal perchlorate test. Did not note a second variant. Variant was absent from 100 control chromosomes-no family/race info
PubMed:10700480
109 patients from 100 families with nonsyndromic hearing loss and EVA. 50 control individuals, study in France. The variant was seen in one affected patient without a second variant.
PubMed:16570074
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
PS3
The variant did not have an impact on the localization, or the iodide efflux capacity, however not all ion transport functions of the proteins were assessed.
PS4
This variant was found in 3 patients in the published literature. It has also been reported in ClinVar in another case from Prof. Karen Avraham @ Tel Aviv Univ.'s lab with congenital profound HL.
There are 9 cases in the LMM database with HL/HL + EVA and this variant, however one of them also has a pathogenic AD KCNQ4 variant so this proband was not counted.
Reardon 1/114 alleles in HL+ EVA cohort
Albert 1/218 alleles in HL + EVA cohort
Sloan Heggen: 1/2238 in HL cohort
LMM internal 5/3884 SLC26A4 tested alleles as of last NVA
8/6454 Alleles Tested in HL/HL+EVA cohorts
vs.
gnomAD: 22/126640 European alleles in gnomAD. AND 52/10150 Ashkenazi alleles in gnomAD = 74/136790 ~ 67/123456
In contingency table: 8 to 6446 vs 67 to 123389 p = 0.0448. Applied Moderate evidence.
Note: if you add in the internal proband with the KCNQ4 variant the significance is higher but it doesn't seem logical to use a proband with alternate cause in this exercise. Also, Karen Avraham's proband was not counted here because the denominator is unknown.
I removed this criteria (was previously scored as PS4_Moderate), but we did not use it in our final classification listed in the Human Mutation manuscript. - Andrea 7.31.18
1119 patients with hearing loss tested. Found one compound heterozygote with this variant in trans with a splicing c.-4+1G>C variant with severe to profound hearing loss, but not noted if they tested temporal bone imaging. Shouldn't be used for PM3, as the splice variant is VUS.
PubMed:26969326
57 EVA patients screened for SLC26A4. Found in one patinet with HL and EVA but a normal perchlorate test. Did not note a second variant. Variant was absent from 100 control chromosomes-no family/race info.
PubMed:10700480
109 patients from 100 families with nonsyndromic hearing loss and EVA. 50 control individuals, study in France. The variant was seen in one affected patient without a second variant.
PubMed:16570074
PP2
z=-3.23
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