ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.298A>G (p.Thr100Ala)

gnomAD frequency: 0.00001  dbSNP: rs745901803
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000631270 SCV000752298 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2024-01-12 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 100 of the VHL protein (p.Thr100Ala). This variant is present in population databases (rs745901803, gnomAD 0.02%). 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: 526674). 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 80%. 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.
CeGaT Center for Human Genetics Tuebingen RCV000997987 SCV001153779 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000997987 SCV001811545 uncertain significance not provided 2022-01-26 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 a pathogenic or benign germline variant to our knowledge; Also known as c.511A>G, p.T171A; Also known as p.T141A; This variant is associated with the following publications: (PMID: 20151405, 7591282)
Sema4, Sema4 RCV002255483 SCV002534157 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-20 criteria provided, single submitter curation
Ambry Genetics RCV002255483 SCV002751451 likely benign Hereditary cancer-predisposing syndrome 2023-01-03 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics RCV002477380 SCV002789633 uncertain significance Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma 2021-11-17 criteria provided, single submitter clinical testing

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