Evidence Repository - Clinical Genome Resources

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_000441.2(SLC26A4):c.1204G>A (p.Val402Met)

CA261400

43495 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7741be8f-b9df-4fc1-9f8d-ebe650c2fce1

Approved on: 2020-02-19

Published on: 2020-02-19

HGVS expressions

NM_000441.2:c.1204G>A

NM_000441.2(SLC26A4):c.1204G>A (p.Val402Met)

NM_000441.1:c.1204G>A

ENST00000265715.7:c.1204G>A

NC_000007.14:g.107690178G>A

CM000669.2:g.107690178G>A

NC_000007.13:g.107330623G>A

CM000669.1:g.107330623G>A

NC_000007.12:g.107117859G>A

NG_008489.1:g.34544G>A

Pathogenic

PM3_Strong PS3_Supporting PP3 PP1 PP4 PM2

Evidence Links 1

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The p.Val402Met variant in SLC26A4 was absent from gnomAD v2.1.1 and v3 (PM2). This variant has been detected in 2 probands with hearing loss. For both patients, a pathogenic or suspected-pathogenic variant was observed in trans (PM3_Strong, PMID:19204907, Partners LMM unpublished data SCV000060082.6). The variant has been reported to segregate in one affected family member (PP1, PMID:19204907). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, LMM unpublished data SCV000060082.6). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:19204907). The REVEL computational prediction analysis tool produced a score of 0.77, which is above the threshold necessary to apply PP3. 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_Strong, PM2, PP1, PP3, PP4, PS3_Supporting).

PM3_Strong

Found in a proband with enlarged vestibular aqueducts in compound heterozygosity with the p.L445W variant in CDH23. The p.L445W variant is absent from gnomAD v2.1.1 and v3 and functional evidence from this publication shows the allele-product is retained within the ER (PMID: 19204907). This variant was also found in a proband with congenital mild to moderate sensorineural hearing loss with the 1437+2T>G splicing variant (P/LP in ClinVar, Variation ID: 43508) confirmed in trans.

PubMed:19204907

PS3_Supporting

This paper shows that the variant displayed an intracellular reticular pattern with no surface expression and was consistent with endoplasmic reticulum retention as described for other SLC26A4 missense mutant products. The variant pendrin was fused at its C-terminus to GFP and expressed in COS-7 cells. See Figure 1. PubMed:19204907

PP3

The REVEL score is 0.77 and the residue is conserved across all mammals and primates in the UCSC database. Some fish and reptiles have an Alanine or Leucine at this position.

PP1

This variant segregated in an affected sibling and gets a LOD score of 0.6 for autosomal recessive segregations which meets criteria to be assigned PP1 at the supporting level.

PP4

Siblings in Family 243 in Choi 2009 both have bilateral EVA and sensorineural hearing loss.

PM2

This variant is absent from gnomAD v2.1.1 and v3.

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