Submissions for variant NM_000551.4(VHL):c.439A>G (p.Ile147Val) (rs1057517560)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411268	SCV000488457	uncertain significance	Von Hippel-Lindau syndrome	2016-04-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000455006	SCV000540658	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in 1 individual; absent from ExAC
Invitae	RCV000470728	SCV000553381	uncertain significance	Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome	2019-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with valine at codon 147 of the VHL protein (p.Ile147Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with bilateral kidney cancer (PMID: 20952280). ClinVar contains an entry for this variant (Variation ID: 371833). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000657081	SCV000568592	uncertain significance	not provided	2017-10-19	criteria provided, single submitter	clinical testing	This variant is denoted VHL c.439A>G at the cDNA level, p.Ile147Val (I147V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant was observed in at least one individual with bilateral renal carcinomas (Petersson 2011). VHL Ile147Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. VHL Ile147Val occurs at a position that is not conserved and is located in the beta-domain and the region involved in binding to the CCT complex (UniProt, Yuen 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Ile147Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000562695	SCV000675798	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-20	criteria provided, single submitter	clinical testing	Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence;Other data supporting pathogenic classification
Fulgent Genetics,Fulgent Genetics	RCV000764459	SCV000895521	uncertain significance	Erythrocytosis, familial, 2; Pheochromocytoma; Von Hippel-Lindau syndrome; Renal cell carcinoma, nonpapillary	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000411268	SCV001304544	uncertain significance	Von Hippel-Lindau syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.