Submissions for variant NM_000441.2(SLC26A4):c.1963A>G (p.Ile655Val)

gnomAD frequency: 0.00001  dbSNP: rs397516424

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000675129	SCV001164252	likely pathogenic	Pendred syndrome	2023-08-27	reviewed by expert panel	curation	The c.1963A>G variant in SLC26A4 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 655 (p.Ile655Val). The highest population minor allele frequency in gnomAD v2.1.1 is .005% (2/34558) in the Latino population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and enlarged vestibular aqueducts (PP4; Laboratory for Molecular Medicine internal data, PMID: 26894580). In one of those probands, a pathogenic variant (VCV000004818.5) was observed in trans, and the variant was observed in the homozygous state in the other proband (PM3; Laboratory for Molecular Medicine internal data, PMID: 26894580).The compound heterozygous individual had an affected sibling in whom both variants segregated (PP1; Laboratory for Molecular Medicine internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was re-reviewed on 8.22.23 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Pendred syndrome. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 8/22/2023 (PM2_Supporting, PP4, PM3, PP1)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036463	SCV000060118	likely pathogenic	Rare genetic deafness	2019-02-06	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Counsyl	RCV000675129	SCV000800699	uncertain significance	Pendred syndrome	2018-04-19	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731331	SCV001984737	likely pathogenic	not specified	2020-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473269	SCV004201807	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-01-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003727609	SCV004538519	likely pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 655 of the SLC26A4 protein (p.Ile655Val). This variant is present in population databases (rs397516424, gnomAD 0.006%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 26894580, 36703223). ClinVar contains an entry for this variant (Variation ID: 43528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003727609	SCV005051080	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SLC26A4: PM3:Strong, PM2, PP4, BP4
GeneDx	RCV003727609	SCV005332646	uncertain significance	not provided	2023-12-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26894580, 36703223, 37811145)
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795954	SCV005417944	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3+PP4