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 - 2.0
- Curation History
- JSON LD for Version 2.0
CA132727
43555 (ClinVar)
Gene: SLC26A4
Condition: Pendred syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 67c2f97e-385f-494a-b06e-701135ace536
Approved on: 2022-11-22
Published on: 2023-01-25
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
Pathogenic
The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence, Benign"Met criteria codes 6
BA1
BS3_Supporting
PP4
PP3
PM3_Very Strong
PP1_Strong
Not Met criteria codes 20
BS2
BS4
BS1
BP2
BP3
BP1
BP4
BP5
BP7
PVS1
PS2
PS4
PS3
PS1
PP2
PM1
PM4
PM5
PM6
PM2
Evidence Links 5
Evidence submitted by expert panel
Hearing Loss VCEP
The c.349C>T variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 117. The filtering allele frequency of the p.Leu117Phe variant is 0.005208 (54/10368 alleles) for Ashkenazi Jewish chromosomes in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong). 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 (LMM) (PP4). The variant 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). A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID: 27771369, 11932316), however, the functional study 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 (BS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VS, PP1_S, PP4, PP3, BS3_P (Hearing Loss VCEP specifications version 2; 11/22/2022).
Met criteria codes
The filtering allele frequency of the p.Leu117Phe variant is 0.005208 (54/10368 alleles) for Ashkenazi Jewish chromosomes in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification.
A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID: 27771369, 11932316), however, the functional study 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 (BS3_Supporting).
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
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:16570074
Patient with EVA and variant
PubMed:10700480
The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3).
This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong).
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
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
The variant 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).
Not Met criteria codes
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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.
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
z=-3.23
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
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
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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.
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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