Submissions for variant NM_000551.4(VHL):c.172C>T (p.Arg58Trp)

gnomAD frequency: 0.00001  dbSNP: rs757781272

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000230639	SCV000285489	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 58 of the VHL protein (p.Arg58Trp). This variant is present in population databases (rs757781272, gnomAD 0.05%). 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: 238102). 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.
Counsyl	RCV000663291	SCV000786533	uncertain significance	Von Hippel-Lindau syndrome	2018-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001012878	SCV001173392	likely benign	Hereditary cancer-predisposing syndrome	2021-08-09	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.
Sema4, Sema4	RCV001012878	SCV002534146	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002500764	SCV002814237	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2022-03-16	criteria provided, single submitter	clinical testing
GeneDx	RCV003151759	SCV003840875	uncertain significance	not provided	2023-03-07	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 pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24969085)
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV000663291	SCV004035059	uncertain significance	Von Hippel-Lindau syndrome	2023-06-10	criteria provided, single submitter	clinical testing