ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.313A>G (p.Thr105Ala)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002461894 SCV002756958 uncertain significance not provided 2022-05-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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
Labcorp Genetics (formerly Invitae), Labcorp RCV003775478 SCV004575779 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 105 of the VHL protein (p.Thr105Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1800755). 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 VHL protein function with a positive predictive value of 95%. 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.
Ambry Genetics RCV004681483 SCV005179658 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-20 criteria provided, single submitter clinical testing The p.T105A variant (also known as c.313A>G), located in coding exon 1 of the VHL gene, results from an A to G substitution at nucleotide position 313. The threonine at codon 105 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.

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