Submissions for variant NM_000441.2(SLC26A4):c.2T>C (p.Met1Thr)

gnomAD frequency: 0.00009  dbSNP: rs111033302

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036489	SCV000060144	pathogenic	Rare genetic deafness	2017-11-22	criteria provided, single submitter	clinical testing	The c.2T>C (p.Met1?) variant in SLC26A4 has been reported in at least 6 individu als with hearing loss and EVA, all of whom were compound heterozygous (Shears 20 04, Gardner 2006, Dai 2009, Choi 2009, Huang 2011, Ladsous 2014, LMM data). It h as been identified in 0.01% (14/87438) of European chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033302). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency for recessive hearing loss . This variant affects the translation initiation start codon (ATG) and is there fore predicted to disrupt translation. In vitro functional studies provide some evidence that the c.2T>C variant may impact protein function (Choi 2009). Additi onally, a different variant in the translation initiation start codon (c.3G>C) h as also been reported in an individual with hearing loss and EVA, supporting tha t changes to this codon are not tolerated. In summary, this variant meets crite ria to be classified as pathogenic for hearing loss in an autosomal recessive ma nner based on the predicted impact of the variant and multiple occurrences with pathogenic SLC26A4 variants in individuals with hearing loss. ACMG/AMP Criteria applied: PVS1; PM3_VeryStrong; PP4.
Invitae	RCV000797012	SCV000936550	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. This variant is present in population databases (rs111033302, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with nonsyndromic sensorineural hearing loss and enlargement of vestibular aqueduct (PMID: 19204907, 19509082, 21961810, 23965030, 25372295, 27997596). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43553). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects SLC26A4 function (PMID: 19204907). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001273161	SCV001481210	pathogenic	Pendred syndrome	2019-10-11	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 14679580, 19204907, 21961810, 24224479]
Baylor Genetics	RCV001329893	SCV001521449	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2020-01-03	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Neurogenetic Laboratory, Second Faculty of Medicine, Charles University	RCV001329893	SCV001571601	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000797012	SCV001873704	pathogenic	not provided	2023-08-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that variant results in protein retention in the endoplasmic reticulum (Choi et al., 2009); This variant is associated with the following publications: (PMID: 27997596, 25372295, 19509082, 20128824, 15099345, 14679580, 24224479, 28780564, 21961810, 16950989, 23965030, 21704276, 19204907, 31589614, 34062854)
Revvity Omics, Revvity	RCV000797012	SCV002020679	pathogenic	not provided	2021-06-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001329893	SCV002027595	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001273161	SCV002027606	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003114215	SCV003799022	pathogenic	SLC26A4-related disorder	2022-10-03	criteria provided, single submitter	clinical testing	PVS1_Strong, PS3, PM3_Strong
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001273161	SCV003800763	pathogenic	Pendred syndrome	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 172798 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (6.9e-05 vs 0.0035), allowing no conclusion about variant significance. c.2T>C has been reported in the literature in individuals affected with Enlargement of the Vestibular aqueduct and Hearing loss, usually associated with Pendred Syndrome( Example: Alber_2006, Choi_2009, Siem_2010, Sloan-Heggen_2016, Smits_2022, Gardner_2006 etc). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Choi_2009) indicating the protein was retained within the endoplasmic reticulum with no surface expression. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV001329893	SCV004024517	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-06-21	criteria provided, single submitter	clinical testing	This SLC26A4 variant (rs111033302) is rare (<0.1%) in a large population dataset (gnomAD: 16/204190 total alleles; MAF 0.008%; no homozygotes) and has been reported in ClinVar. This variant alters the initiation codon and is predicted to result either in absence of the protein or alteration of the encoded protein due to translation initiation at a downstream methionine codon. In vitro functional studies of p.Met1Thr using transfected cells showed the protein was retained within the endoplasmic reticulum with no surface expression. This SLC26A4 variant has been reported in unrelated individuals with hearing loss and EVA, usually in a compound heterozygous state with a different pathogenic variant. We consider c.2T>C (p.Met1Thr) to be pathogenic for DFNB4.
PreventionGenetics, part of Exact Sciences	RCV003421948	SCV004117269	pathogenic	SLC26A4-related condition	2023-01-19	criteria provided, single submitter	clinical testing	The SLC26A4 c.2T>C variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported in individuals with autosomal recessive Pendred syndrome or nonsyndromic enlarged vestibular aqueduct (NSEVA) (reported as "M1T" in Prasad et al. 2004. PubMed ID: 14679580; Choi et al. 2009. PubMed ID: 19204907; Ladsous et al. 2014. PubMed ID: 24224479). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-107302088-T-C). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/43553). Given all the evidence, we interpret c.2T>C (p.Met1?) as pathogenic.
Natera, Inc.	RCV001273161	SCV001455790	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000797012	SCV001955244	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000797012	SCV001965580	pathogenic	not provided		no assertion criteria provided	clinical testing