ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.167C>G (p.Ala56Gly)

gnomAD frequency: 0.00004  dbSNP: rs752980085
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409162 SCV000487943 uncertain significance Von Hippel-Lindau syndrome 2015-12-04 criteria provided, single submitter clinical testing
Invitae RCV000530730 SCV000626882 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2022-10-01 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 56 of the VHL protein (p.Ala56Gly). This variant is present in population databases (rs752980085, gnomAD 0.01%). 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: 371800). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 RCV001012691 SCV001173176 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-25 criteria provided, single submitter clinical testing The p.A56G variant (also known as c.167C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 167. The alanine at codon 56 is replaced by glycine, an amino acid with similar properties. This variant has been reported in a thrombosis patient who underwent hereditary erythrocytosis multi-gene panel testing (Oliveira JL et al. Am J Hematol. 2018 May 23). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4 RCV001012691 SCV002534145 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-27 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002481266 SCV002796942 uncertain significance Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma 2022-02-11 criteria provided, single submitter clinical testing
GeneDx RCV000782251 SCV004022806 uncertain significance not provided 2023-07-17 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; Observed in individuals with breast cancer or erythrocytosis in published literature (Oliveira et al., 2018; McDonald et al., 2022); This variant is associated with the following publications: (PMID: 29790589, 35142155, 36315513)
Baylor Genetics RCV003470356 SCV004206464 uncertain significance Chuvash polycythemia 2023-10-19 criteria provided, single submitter clinical testing
Gharavi Laboratory, Columbia University RCV000782251 SCV000920741 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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