Submissions for variant NM_000551.4(VHL):c.256C>G (p.Pro86Ala)

dbSNP: rs398123481

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723702	SCV000111078	pathogenic	not provided	2013-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000079208	SCV000697489	likely pathogenic	Von Hippel-Lindau syndrome	2016-01-29	criteria provided, single submitter	clinical testing	Variant summary: This c.256C>G variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ala in HIFalfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 2/102226 control chromosomes including the broad and large population from ExAC at a frequency of 0.0000196, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208) in this gene. In literature, this variant has been reported in five independent patients with Von Hippel-Lindau disease or related cancers. Other missense changes at this codon are also reported in association VHL disease, namely p.P86R, p.P86L and p.P86S, suggesting that this codon is likely to be a mutational hot-spot. One clinical lab (via ClinVar) and one reputable database classify this variant as pathogenic. Taken together, this variant is currently classified as Likely Pathogenic.
Invitae	RCV001227827	SCV001400203	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2019-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline with alanine at codon 86 of the VHL protein (p.Pro86Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 17102082, 27034144, 7728151, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.469C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 93327). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8634692, 9829912, 19464396, 27057652, 27527340, 11257211, 19408298). 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	RCV000079208	SCV000264683	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing