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

gnomAD frequency: 0.00001  dbSNP: rs745901803

Total submissions: 8

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	2025-01-06	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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
Myriad Genetics, Inc.	RCV004788047	SCV005406046	likely benign	Von Hippel-Lindau syndrome	2024-08-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000997987	SCV005622759	uncertain significance	not provided	2024-10-17	criteria provided, single submitter	clinical testing	The VHL c.298A>G (p.Thr100Ala) variant has been reported in the published literature in somatic tissue samples from individual with renal cell carcinoma (RCC) (PMIDs: 32982583 (2020), 7591282 (1995)), however this variant has not been reported to be germline in individuals with VHL-related conditions. Functional studies demonstrated that this variant has an inconclusive effect on protein function (PMID: 38969834 (2024)). The frequency of this variant in the general population, 0.00017 (5/30162 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.