ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.229T>C (p.Cys77Arg)

dbSNP: rs1269136170
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002040545 SCV002297799 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2021-02-11 criteria provided, single submitter clinical testing 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. 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. This variant has not been reported in the literature in individuals with VHL-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 77 of the VHL protein (p.Cys77Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.
Baylor Genetics RCV004571966 SCV005055810 uncertain significance Chuvash polycythemia 2023-11-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV004947038 SCV005534961 uncertain significance Hereditary cancer-predisposing syndrome 2024-12-04 criteria provided, single submitter clinical testing The p.C77R variant (also known as c.229T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 229. The cysteine at codon 77 is replaced by arginine, an amino acid with highly dissimilar properties. In a saturation genome editing assay, this variant was reported as functionally neutral (Buckley M et al. Nat Genet, 2024 Jul;56:1446-1455). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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