ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.2170G>A (p.Asp724Asn)

gnomAD frequency: 0.00002  dbSNP: rs994170964
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668584 SCV000793211 uncertain significance Pendred syndrome 2017-08-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330882 SCV004037946 uncertain significance not specified 2023-08-17 criteria provided, single submitter clinical testing Variant summary: SLC26A4 c.2170G>A (p.Asp724Asn) results in a conservative amino acid change located in the STAS domain (IPR002645) 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 2e-05 in 150994 control chromosomes (gnomAD). c.2170G>A has been reported in the literature as a biallelic genotype in at least one individual affected with Pendred Syndrome (Blons_2004). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different missense variant occuring at the same codon has been previously classified as pathogenic/likely pathogenic (p.Asp724Gly, ClinVar: 228396), suggesting this residue may be of clinical significance. The following publication has been ascertained in the context of this evaluation (PMID: 15355436). One ClinVar submitter has assessed the variant since 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV003558498 SCV004295507 pathogenic not provided 2023-10-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 724 of the SLC26A4 protein (p.Asp724Asn). This variant is present in population databases (no rsID available, gnomAD 0.03%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 15355436). ClinVar contains an entry for this variant (Variation ID: 553188). 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 with a positive predictive value of 95%. This variant disrupts the p.Asp724 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14679580, 15811013, 19017801, 24224479). 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.

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