Submissions for variant NM_000551.4(VHL):c.150C>G (p.Ala50=)

gnomAD frequency: 0.00070  dbSNP: rs61751580

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen VHL Variant Curation Expert Panel, ClinGen	RCV001150099	SCV005187305	benign	Von Hippel-Lindau syndrome	2024-06-25	reviewed by expert panel	curation	The variant NM_000551.4(VHL):c.150C>G (p.Ala50=) is a synonymous (silent) variant that is not predicted by SpliceAI or VarSeak to impact splicing. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.0.0 is 0.001000 (1222/1163922 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036538	SCV000060193	likely benign	not specified	2010-10-05	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in two individuals with tumors consistent with VHL syndrome. It was reported in the tumor of one individual wit h a central nervous system hemangioblastoma and in the blood of a second individ ual with a pheochromocytoma (Cybulski 2004, Meyer-Rochow 2009). However, this va riant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. However, on rare occasions, nucleotide changes that do not result in amino acid changes can be as sociated with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083936	SCV000166402	benign	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000036538	SCV000211835	benign	not specified	2014-09-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000161100	SCV000213981	likely benign	Hereditary cancer-predisposing syndrome	2014-11-12	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.
PreventionGenetics, part of Exact Sciences	RCV000679018	SCV000805321	likely benign	not provided	2017-07-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036538	SCV000918338	benign	not specified	2018-05-07	criteria provided, single submitter	clinical testing	Variant summary: VHL c.150C>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 0.0005 in 211956 control chromosomes (gnomAD). The observed variant frequency is approximately 24-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in VHL causing Von Hippel-Lindau Syndrome phenotype (2.1e-05), strongly suggesting that the variant is benign. The variant, c.150C>G, has been reported in the literature in individuals affected with Von Hippel-Lindau Syndrome (Meyer-Rochow_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Von Hippel-Lindau Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Clinvar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "benign." Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000679018	SCV001153777	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	VHL: BP4, BP7
Illumina Laboratory Services, Illumina	RCV001150099	SCV001311111	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Sema4, Sema4	RCV000161100	SCV002534142	benign	Hereditary cancer-predisposing syndrome	2021-02-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000036538	SCV002552397	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001150099	SCV004360951	benign	Von Hippel-Lindau syndrome	2022-09-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679018	SCV001809521	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000679018	SCV001932576	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genomics Labs, University Health Network	RCV001150099	SCV001950148	likely benign	Von Hippel-Lindau syndrome	2017-05-29	no assertion criteria provided	clinical testing