Submissions for variant NM_000441.2(SLC26A4):c.1337A>G (p.Gln446Arg)

dbSNP: rs768471577

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665266	SCV000789357	likely pathogenic	Pendred syndrome	2017-02-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001227582	SCV001399944	pathogenic	not provided	2023-08-19	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 446 of the SLC26A4 protein (p.Gln446Arg). This variant is present in population databases (rs768471577, gnomAD 0.06%). This missense change has been observed in individuals with Pendred syndrome or non-syndromic deafness (PMID: 11932316, 19287372, 24949729, 25394566, 25491636, 27573290). ClinVar contains an entry for this variant (Variation ID: 550505). 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: 11932316). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001809737	SCV002058348	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550505, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11932316, PS3_S).The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000076, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.914, 3CNET: 0.817, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). 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	RCV000665266	SCV002103491	pathogenic	Pendred syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1337A>G (p.Gln446Arg) 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 7.6e-05 in 250738 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00059 vs 0.0035), allowing no conclusion about variant significance. c.1337A>G has been reported in the literature in the homozygous or compound heterozygous state in multiple families affected with hearing loss (e.g. Taylor_2002, Rehman_2015, Naz_2017, Richard_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant failed to reach the cell membrane and colocalized with the endoplasmic reticulum, and had lost its ability to transport iodide (Taylor_2002). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002499147	SCV002813940	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2022-03-23	criteria provided, single submitter	clinical testing
UAEU Genomics Laboratory, United Arab Emirates University	RCV001809737	SCV003926560	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-03-23	criteria provided, single submitter	research	The missense variant NM_000441.2(SLC26A4):c.1337A>G (p.Gln446Arg) has been reported in homozygous state in several families affected with hearing loss (PMID: 30303587, PMID: 19287372, PMID: 24949729). This variant is observed in 18/30616 (0.06%) alleles from individuals of South Asian background in the gnomAD database, but was not seen in the homozygous state. Computational prediction tools and conservation analysis indicate that this change is damaging to the protein. Published in vitro functional studies indicated that this variant leads to mis-localization of the protein and loss of pendrin iodide transport (PMID: 11932316). This variant has been confirmed to occur in trans (in a compound heterozygous state) with a second variant in the patient and his sibling. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001809737	SCV004201924	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-12-03	criteria provided, single submitter	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291350	SCV001479824	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research