ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.412G>C (p.Val138Leu)

dbSNP: rs111033199
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672001 SCV000797052 likely pathogenic Pendred syndrome 2018-01-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001855572 SCV002240194 pathogenic not provided 2022-11-03 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val138 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618166, 11932316, 12788906, 21551164, 23273637, 24224479, 26969326). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 19645628). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. ClinVar contains an entry for this variant (Variation ID: 556058). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 18665027, 19645628, 25488846). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 138 of the SLC26A4 protein (p.Val138Leu).
3billion RCV003152725 SCV003841669 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19645628). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000556058) and a different missense change at the same codon (p.Val138Phe / ClinVar ID: VCV000004835) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV003152725 SCV004201923 likely pathogenic Autosomal recessive nonsyndromic hearing loss 4 2023-05-31 criteria provided, single submitter clinical testing

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