Submissions for variant NM_000551.4(VHL):c.233A>C (p.Asn78Thr)

dbSNP: rs5030804

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000679024	SCV000805329	pathogenic	not provided	2014-04-16	criteria provided, single submitter	clinical testing
Invitae	RCV000805326	SCV000945278	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-02-05	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 78 of the VHL protein (p.Asn78Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 8956040, 18446368; Invitae). ClinVar contains an entry for this variant (Variation ID: 223168). 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 disrupts the p.Asn78 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 8956040, 12114495, 15109448, 15300849, 19464396, 23842656). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208838	SCV000264677	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing