Submissions for variant NM_000551.4(VHL):c.5C>T (p.Pro2Leu)

gnomAD frequency: 0.00008  dbSNP: rs111246617

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161089	SCV000211824	likely benign	not provided	2019-11-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29790589, 10612827)
Invitae	RCV000168429	SCV000219126	likely benign	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000294881	SCV000439631	uncertain significance	Von Hippel-Lindau syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV000492422	SCV000580966	likely benign	Hereditary cancer-predisposing syndrome	2020-06-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781920	SCV000920339	uncertain significance	not specified	2017-10-23	criteria provided, single submitter	clinical testing	Variant summary: The VHL c.5C>T (p.Pro2Leu) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 12/164682 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000189 (12/63398). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic VHL variant (0.0000208), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as a VUS - possibly benign variant, until additional evidence becomes available.
Sema4, Sema4	RCV000492422	SCV002534194	likely benign	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003416030	SCV004115034	uncertain significance	VHL-related disorder	2023-06-14	criteria provided, single submitter	clinical testing	The VHL c.5C>T variant is predicted to result in the amino acid substitution p.Pro2Leu. This variant has been reported as a variant of uncertain significance in the heterozygous state in two patients with hereditary erythrocytosis (Oliveira et al. 2018. PubMed ID: 29790589). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-10183536-C-T) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182981/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781920	SCV004243129	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000161089	SCV004811530	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	VHL: PM2
All of Us Research Program, National Institutes of Health	RCV000294881	SCV004841628	uncertain significance	Von Hippel-Lindau syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with erythrocytosis (PMID: 29790589). This variant has been identified in 14/171178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.