Submissions for variant NM_000551.4(VHL):c.154G>A (p.Glu52Lys)

dbSNP: rs373068386

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000148923	SCV000190680	uncertain significance	Von Hippel-Lindau syndrome	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Invitae	RCV000227809	SCV000285488	likely benign	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001704076	SCV000293309	likely benign	not provided	2021-03-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 11257211, 25637381, 27651169, 26211615, 9829912, 24138046, 12202531, 24055113, 21463266, 15300849, 18836774, 19574279, 18416845)
Ambry Genetics	RCV000575111	SCV000675792	likely benign	Hereditary cancer-predisposing syndrome	2018-04-26	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.
Counsyl	RCV000148923	SCV000785754	uncertain significance	Von Hippel-Lindau syndrome	2017-11-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000148923	SCV001136309	benign	Von Hippel-Lindau syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575111	SCV002534143	likely benign	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000148923	SCV002584740	uncertain significance	Von Hippel-Lindau syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The VHL c.154G>A (p.Glu52Lys) missense change has a maximum subpopulation frequency of 0.075% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with Von Hippel-Lindau disease (PMID: 12202531). In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465537	SCV002760267	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001704076	SCV003820403	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415985	SCV004116597	uncertain significance	VHL-related disorder	2022-12-22	criteria provided, single submitter	clinical testing	The VHL c.154G>A variant is predicted to result in the amino acid substitution p.Glu52Lys. This variant has been reported in patients with von Hippel-Lindau disease with and without renal involvement (Dollfus et al. 2002. PubMed ID: 12202531; Supplementary Table S1, Gallou et al. 2004. PubMed ID: 15300849). In addition, this variant has been identified and classified as a variant of uncertain significant in a study analyzing incidental findings in patients of European and African-ancestry that participated in the National Heart, Lung, and Blood Institute Exome Sequencing Project (Supplementary Table 1, Amendola et al. 2015. PubMed ID: 25637381; Supplementary Table 1, Dorschner et al. 2013. PubMed ID: 24055113). This variant has also been reported in an individual with hepatoblastoma (Aguiar et al. 2022. PubMed ID: 35495172). However, this variant is reported in 0.075% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-10183685-G-A), which may be too common to be a primary cause of disease. This variant has interpretations of likely benign, uncertain, and likely pathogenic in ClinVar (ncbi.nlm.nih.gov/clinvar/variation/161402) Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV001704076	SCV004146915	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	VHL: PS4:Moderate
Color Diagnostics, LLC DBA Color Health	RCV000148923	SCV004360952	uncertain significance	Von Hippel-Lindau syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 52 of the VHL protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in families and individuals affected with Von Hippel-Lindau disease (PMID: 12202531, 15300849). This variant has been identified in 19/222880 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.
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843484	SCV002103100	likely pathogenic	Hepatoblastoma		flagged submission	research
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV002467589	SCV002764242	likely pathogenic	Enchondromatosis		flagged submission	research