Submissions for variant NM_000441.2(SLC26A4):c.439A>G (p.Met147Val)

gnomAD frequency: 0.00001  dbSNP: rs760413427

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389158	SCV001590424	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 147 of the SLC26A4 protein (p.Met147Val). This variant is present in population databases (rs760413427, gnomAD 0.01%). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 14508505, 15679828, 21961810). ClinVar contains an entry for this variant (Variation ID: 691508). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 18310264, 20826203). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001004625	SCV002572814	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC26A4-related disorder (ClinVar ID: VCV000691508 / PMID: 14508505). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 23918157). Different missense changes at the same codon (p.Met147Leu, p.Met147Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000556648 , VCV001067001). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235420	SCV003934512	pathogenic	Pendred syndrome	2023-05-26	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.439A>G (p.Met147Val) results in a conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251464 control chromosomes (gnomAD). c.439A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Hearing Loss w/ Enlarged Vestibular Aqueducts (e.g. Miyagawa_2014, Rah_2015, Tian_2021). These data indicate that the variant is very likely to be associated with disease. Functional assays using HEK293T cells show that the variant is not present on the plasma membrane and has impaired anion transport activity (e.g. Yoon_2008, Wasano_2020). The following publications have been ascertained in the context of this evaluation (PMID: 24599119, 25488846, 34170635, 31599023, 18310264). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as pathogenic, and one reports it as a loss of function variant. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001389158	SCV004168915	pathogenic	not provided	2023-04-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on protein folding resulting in intracellular retention and a loss of plasma membrane trafficking (Ishihara et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27771369, 30275481, 32877901, 23918157, 31581539, 18310264, 31599023, 15679828, 14508505, 21961810, 34170635, 20826203)
Baylor Genetics	RCV001004625	SCV004201940	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-18	criteria provided, single submitter	clinical testing
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004625	SCV000994869	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	clinical testing	in vitro experiment
Precision Medicine Center, Zhengzhou University	RCV001004625	SCV001572603	pathogenic	Autosomal recessive nonsyndromic hearing loss 4		no assertion criteria provided	research	PP1: Segregation in one affected relative PM2_Supporting: gnomAD East Asian allele frequency = 0.0001087< 0.00007 PM3_VeryStrong: Pathogenic mutation confirmed in trans in three patients and phase unknown in six patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene