Submissions for variant NM_000441.2(SLC26A4):c.1238A>G (p.Gln413Arg)

gnomAD frequency: 0.00001  dbSNP: rs142498437

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411469	SCV000485281	likely pathogenic	Pendred syndrome	2016-01-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216381	SCV001388177	pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 413 of the SLC26A4 protein (p.Gln413Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 20137612, 21961810, 23185506, 24248179, 25015771, 25266519, 25290043, 25372295, 26752218). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 370080). 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. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 26752218). This variant disrupts the p.Gln413 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18285825, 19017801). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000411469	SCV002026920	likely pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567873	SCV005056830	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411469	SCV005203518	pathogenic	Pendred syndrome	2024-07-16	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1238A>G (p.Gln413Arg) 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 250842 control chromosomes. c.1238A>G has been reported in the literature in multiple individuals affected with hearing loss (examples: Wang_2014, Yazdanpanahi_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25290043, 25015771). ClinVar contains an entry for this variant (Variation ID: 370080). Based on the evidence outlined above, the variant was classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796160	SCV005418684	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3_Supporting+PM3_VeryStrong
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291348	SCV001479822	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research