Submissions for variant NM_000551.4(VHL):c.445G>C (p.Ala149Pro)

dbSNP: rs587780077

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853329	SCV002237232	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2021-05-28	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of von-Hippel Lindau syndrome (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 223214). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala149 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9435426, 23673869, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 149 of the VHL protein (p.Ala149Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208855	SCV000264740	uncertain significance	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing