ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.572C>T (p.Ala191Val)

gnomAD frequency: 0.00002  dbSNP: rs372875358
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000036498 SCV000060153 uncertain significance not specified 2012-01-20 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ala191Val varia nt in SLC26A4 has not been reported in the literature nor previously identified by our laboratory. The variant has been identified in 0.0142% (1/7020) of Europe an American chromosomes by the NHBLI Exome sequencing project in a broad populat ion (http://evs.gs.washington.edu/EVS). This residue is not highly conserved in mammals or other species and computational analyses (biochemical amino acid prop erties, homology, PolyPhen2, AlignGVGD) do not suggest a high likelihood of impa ct to the protein. However, this information is not predictive enough to rule ou t pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time; however, we would lean towards a more l ikely benign role based upon the lack of conservation of the amino acid residue.
GeneDx RCV001799613 SCV002044255 uncertain significance not provided 2021-06-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Invitae RCV001799613 SCV003026654 likely pathogenic not provided 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 191 of the SLC26A4 protein (p.Ala191Val). This variant is present in population databases (rs372875358, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Pendred syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43561). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Natera, Inc. RCV001831651 SCV002079974 uncertain significance Pendred syndrome 2019-11-11 no assertion criteria provided clinical testing

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