Submissions for variant NM_000551.4(VHL):c.639T>C (p.Asp213=)

gnomAD frequency: 0.00004  dbSNP: rs775624944

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000342034	SCV000439638	uncertain significance	Von Hippel-Lindau syndrome	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000679045	SCV000515250	likely benign	not provided	2020-04-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081661	SCV000563221	likely benign	Chuvash polycythemia; Von Hippel-Lindau syndrome	2025-01-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679045	SCV000805360	likely benign	not provided	2017-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001025221	SCV001187368	likely benign	Hereditary cancer-predisposing syndrome	2018-04-25	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.
All of Us Research Program, National Institutes of Health	RCV000342034	SCV004841679	likely benign	Von Hippel-Lindau syndrome	2023-12-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238930	SCV005884129	benign	not specified	2024-12-11	criteria provided, single submitter	clinical testing	Variant summary: VHL c.639T>C results in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing (TrAP). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 249864 control chromosomes. The observed variant frequency is approximately 1.92 fold of the estimated maximal expected allele frequency for a pathogenic variant in VHL causing Von Hippel-Lindau Syndrome phenotype (2.1e-05). To our knowledge, no occurrence of c.639T>C in individuals affected with Von Hippel-Lindau Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 342404). Based on the evidence outlined above, the variant was classified as benign.