Submissions for variant NM_000551.4(VHL):c.477del (p.Glu160fs)

dbSNP: rs730882020

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen VHL Variant Curation Expert Panel, ClinGen	RCV000208863	SCV005187289	pathogenic	Von Hippel-Lindau syndrome	2024-06-25	reviewed by expert panel	curation	This variant has been identified in at least 9 unrelated probands (and other related family members not counted within each) all meeting Danish VHL criteria, from literature evaluated in both CIViC and Hypothes.is VHL datasets. CIViC EIDs (https://civicdb.org): 8292;7606;5776;9374;6806;6538. This corresponds to Strong evidence (5-15 probands) (PS4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 3 probands/families meeting meeting either VHL Type 1 or affected with VHL-related cancers. (2.25 points, PS4_Moderate; PMID: 11114638, 12114494, 9829911). In summary, this variant meets the criteria to be classified as Pathogenic 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).
GeneDx	RCV000161061	SCV000211793	pathogenic	not provided	2019-08-21	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 22825683, 19755989, 9829911, 20454689, 20151405, 19996202)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687350	SCV000814913	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu160Serfs*10) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the VHL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 982991). This variant is also known as c.688delA. ClinVar contains an entry for this variant (Variation ID: 182959). This variant disrupts a region of the VHL protein in which other variant(s) (p.Tyr175*) have been determined to be pathogenic (PMID: 9829912, 12202531, 15300849; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001406	SCV001158640	pathogenic	not specified	2019-01-17	criteria provided, single submitter	clinical testing	The VHL c.477delA; p.Glu160fs variant (rs730882020), also reported as 688delA, is reported in the literature in a family affected with von Hippel-Lindau syndrome (Stolle 1998) and in a renal cell carcinoma sample (Taylor 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 182959). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Stolle C et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12(6):417-23. Taylor C et al. Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma. Int J Oncol. 2012 Oct;41(4):1229-40.
Baylor Genetics	RCV003467274	SCV004208791	pathogenic	Chuvash polycythemia	2022-12-08	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208863	SCV000264755	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing