Submissions for variant NM_000551.4(VHL):c.614G>A (p.Arg205His)

gnomAD frequency: 0.00003  dbSNP: rs777130107

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481472	SCV000571135	likely benign	not provided	2019-03-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25911330, 22895193, 24969085, 28422758, 10857749)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631259	SCV000752287	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 205 of the VHL protein (p.Arg205His). This variant is present in population databases (rs777130107, 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: 421823). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
PreventionGenetics, part of Exact Sciences	RCV000481472	SCV000805359	uncertain significance	not provided	2018-03-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764460	SCV000895522	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024946	SCV001187044	likely benign	Hereditary cancer-predisposing syndrome	2018-11-27	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.
Myriad Genetics, Inc.	RCV004787783	SCV005406101	likely benign	Von Hippel-Lindau syndrome	2024-08-26	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.