Submissions for variant NM_000441.2(SLC26A4):c.841G>A (p.Val281Ile)

gnomAD frequency: 0.00009  dbSNP: rs727505080

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156520	SCV000206239	likely benign	not specified	2014-05-06	criteria provided, single submitter	clinical testing	Val281Ile in exon 7 of SLC26A4: This variant has been identified in one individu al with hearing loss who carried a second pathogenic variant in SLC26A4 (Pourova 2010). However, this variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Many species, inclu ding several primates, carry an isoleucine (Ile) at this position despite high n earby amino acid conservation. In addition, computational prediction tools do no t suggest a high likelihood of impact to the protein.
Illumina Laboratory Services, Illumina	RCV000295053	SCV000466083	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000352007	SCV000466084	uncertain significance	Pendred syndrome	2016-07-27	criteria provided, single submitter	clinical testing	The SLC26A4 c.841G>A (p.Val281Ile) variant is a missense variant that has been reported in a compound heterozygous state with a second, known pathogenic splicing variant in one individual with Pendred syndrome (Pourova et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.00174 in the Latino population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Val281Ile variant is thus classified as a variant of unknown significance but suspicious for pathogenicity for Pendred syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics	RCV000352007	SCV001137435	benign	Pendred syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000295053	SCV002027007	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000352007	SCV002027018	uncertain significance	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857543	SCV002270639	likely benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000156520	SCV002766033	uncertain significance	not specified	2022-11-08	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.841G>A (p.Val281Ile) results in a conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251110 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00023 vs 0.0035), allowing no conclusion about variant significance. c.841G>A has been reported in the literature in an individual affected with Pendred Syndrome (example: Pourova_2010). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV001857543	SCV003825639	uncertain significance	not provided	2021-04-26	criteria provided, single submitter	clinical testing