Submissions for variant NM_000441.2(SLC26A4):c.1204G>A (p.Val402Met) (rs397516414)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171536	SCV001334321	pathogenic	Pendred syndrome	2020-02-19	reviewed by expert panel	curation	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patients, a pathogenic or suspected-pathogenic variant was observed in trans (PM3_Strong, PMID:19204907, Partners LMM unpublished data SCV000060082.6).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of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, LMM unpublished data SCV000060082.6).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).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000036427	SCV000060082	likely pathogenic	Rare genetic deafness	2016-11-17	criteria provided, single submitter	clinical testing	The p.Val402Met variant in SLC26A4 has been identified in the compound heterozyg ous state with another pathogenic variant in SLC26A4 in two siblings with enlarg ed vestibular aqueduct (Choi 2009) and in an individual with hearing loss tested by our laboratory. This variant has not been reported in large population studi es. A study has shown that the p.Val402Met variant may impact protein function ( Choi 2009). In summary, although additional studies are required to fully establ ish its clinical significance, this variant is likely pathogenic.
Illumina Clinical Services Laboratory,Illumina	RCV000259862	SCV000466100	uncertain significance	SLC26A4-Related Disorders	2016-07-27	criteria provided, single submitter	clinical testing	The SLC26A4 c.1204G>A (p.Val402Met) variant is a missense variant that has been reported in one study, in which it was found in a compound heterozygous state with a second missense variant in two siblings with hearing loss and bilateral enlarged vestibular aqueduct (Choi et al. 2009). The p.Val402Met variant was absent from 172 ethnically matched control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium despite being located in a region of good sequence coverage. Therefore, it is presumed to be rare. Functional studies in COS-7 cells demonstrated that the p.Val402Met variant protein showed improper cellular localization, with endoplasmic reticulum retention compared to the cell surface expression of the wild type protein. The Val402 residue is conserved among SLC26A4 orthologues but not among SLC26A4 paralogues. The evidence for this variant is limited. The p.Val402Met variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.