ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.256C>G (p.Pro86Ala) (rs398123481)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723702 SCV000111078 pathogenic not provided 2013-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 Erythrocytosis, familial, 2; 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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000079208 SCV000264683 likely pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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