7-107661643-T-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000441.2(SLC26A4):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,562,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (ā ā ).
Frequency
Consequence
NM_000441.2 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152258Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000694 AC: 12AN: 172798Hom.: 0 AF XY: 0.0000846 AC XY: 8AN XY: 94532
GnomAD4 exome AF: 0.000152 AC: 214AN: 1410366Hom.: 0 Cov.: 30 AF XY: 0.000129 AC XY: 90AN XY: 698144
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74394
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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 gene product 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. -
Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Published in vitro functional studies demonstrate loss of activity due to protein retention in the endoplasmic reticulum (PMID: 19204907); This variant is associated with the following publications: (PMID: 27997596, 25372295, 19509082, 20128824, 15099345, 14679580, 24224479, 28780564, 21961810, 16950989, 23965030, 21704276, 19204907, 31589614, 34062854, 34515852, 35982127) -
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Pendred syndrome Pathogenic:4
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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] -
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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. -
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:4
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This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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. -
SLC26A4-related disorder Pathogenic:2
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. -
PVS1_Strong, PS3, PM3_Strong -
Rare genetic deafness Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at