ClinVar Miner

Submissions for variant NM_175875.5(SIX5):c.886G>A (p.Ala296Thr)

gnomAD frequency: 0.00009  dbSNP: rs80356462
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001723554 SCV002005566 likely benign not provided 2021-02-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17357085, 31589614)
Revvity Omics, Revvity RCV000009130 SCV003823287 uncertain significance Branchiootorenal syndrome 2 2021-01-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001723554 SCV004266979 uncertain significance not provided 2023-10-16 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 296 of the SIX5 protein (p.Ala296Thr). This variant is present in population databases (rs80356462, gnomAD 0.02%). This missense change has been observed in individual(s) with Branchio-Oto-Renal Syndrome (PMID: 17357085). ClinVar contains an entry for this variant (Variation ID: 8599). 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 not expected to disrupt SIX5 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SIX5 function (PMID: 17357085). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breakthrough Genomics, Breakthrough Genomics RCV001723554 SCV005209694 likely benign not provided criteria provided, single submitter not provided
OMIM RCV000009130 SCV000029347 pathogenic Branchiootorenal syndrome 2 2007-04-01 no assertion criteria provided literature only
GeneReviews RCV000009130 SCV000041680 not provided Branchiootorenal syndrome 2 no assertion provided literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001723554 SCV001957588 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001723554 SCV001965525 likely benign not provided no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004752693 SCV005351904 uncertain significance SIX5-related disorder 2024-03-11 no assertion criteria provided clinical testing The SIX5 c.886G>A variant is predicted to result in the amino acid substitution p.Ala296Thr. This variant has been reported in the heterozygous state in an individual with branchio-oto-renal syndrome (Hoskins et al. 2007. PubMed ID: 17357085). Experimental studies using a yeast two-hybrid assay and a luciferase assay were inconclusive (Hoskins et al. 2007. PubMed ID: 17357085). This variant is reported in 0.017% of alleles in individuals of African descent in gnomAD, including more than 280 heterozygotes in the gnomAD v4.0.0 dataset. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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