Submissions for variant NM_000551.4(VHL):c.485G>T (p.Cys162Phe)

dbSNP: rs397516444

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036548	SCV000697522	pathogenic	Von Hippel-Lindau syndrome	2016-02-04	criteria provided, single submitter	clinical testing	Variant summary: This c.485G>T affects a conserved nucleotide, resulting in amino acid change from Cys to Phe in alfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. The residue p.Cys162 is reported to directly contact with elongins and functional assays show that this variant abrogates the binding to elongin/Cul2 (Ohh_1999, Ohh_2000, Hansen_2002). The variant was also shown to abrogate the ubiquitination and binding to HIF and binding to E-cadherin (Ohh_2000, Hansen_2002, Evans_2007). These findings prove that this variant is functionally defective. This variant was found in 1/121234 control chromosomes including the broad and large populations from ExAC at a frequency of 0.0000082, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208). This variant has been found in at least six independent VHL patients/families. One clinical lab (via ClinVar) has classified this variant as pathogenic. Other likely pathogenic variants (namely, p.C162R, p.C162W, and p.C162Y. p.Cys162TrpfsX12, etc.) have also been reported at this p.C162 residue, suggesting that this codon is likely to be a mutational hot-spot. Taken together, this variant has been classified as a Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513389	SCV003525020	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 10878807, 11331612, 19228690). 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. ClinVar contains an entry for this variant (Variation ID: 43604). This variant is also known as c.698G>T. This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 9452032, 10458336, 20064270). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 162 of the VHL protein (p.Cys162Phe).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000036548	SCV004171480	pathogenic	Von Hippel-Lindau syndrome	2023-10-18	criteria provided, single submitter	clinical testing	The VHL c.485G>T (p.Cys162Phe) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies indicate that this variant disrupts VHL protein function and impairs ability to bind to hypoxia-inducible factor (HIF) (PMID: 34004371, 10878807, 11331612, 11865071, 17060462, 19228690). This variant has been reported in individuals and families with Von Hippel Lindau-related cancers (PMID: 9452032, 20064270). In summary, this variant meets criteria to be classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036548	SCV000060203	pathogenic	Von Hippel-Lindau syndrome	2007-04-18	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000036548	SCV000264759	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing