Submissions for variant NM_000441.2(SLC26A4):c.2029C>T (p.Arg677Trp)

gnomAD frequency: 0.00010  dbSNP: rs397516426

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156486	SCV000206205	uncertain significance	not specified	2014-03-21	criteria provided, single submitter	clinical testing	The Arg677Trp variant in SLC26A4 has not been reported in individuals with heari ng loss or in large population studies. Computational prediction tools and conse rvation analysis do not provide strong support for or against an impact to the p rotein. Additional information is needed to fully assess the clinical significan ce of the Arg677Trp variant.
Illumina Laboratory Services, Illumina	RCV001161292	SCV001323154	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001161293	SCV001323155	uncertain significance	Pendred syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab	RCV001161292	SCV002027023	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001161293	SCV002027024	uncertain significance	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001824289	SCV002074011	uncertain significance	not provided	2022-01-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with and SLC26A4-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 32425884)
Fulgent Genetics, Fulgent Genetics	RCV002484951	SCV002778644	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2022-02-14	criteria provided, single submitter	clinical testing
Invitae	RCV001824289	SCV003446618	likely pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 677 of the SLC26A4 protein (p.Arg677Trp). This variant is present in population databases (rs397516426, gnomAD 0.02%). This missense change has been observed in individual(s) with bilateral deafness with enlarged vestibular aqueducts (PMID: 35249537). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179690). 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.
Natera, Inc.	RCV001161293	SCV002080016	uncertain significance	Pendred syndrome	2020-02-11	no assertion criteria provided	clinical testing