Submissions for variant NM_000551.4(VHL):c.119C>T (p.Pro40Leu)

gnomAD frequency: 0.00004  dbSNP: rs200343185

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen VHL Variant Curation Expert Panel, ClinGen	RCV000662921	SCV005187304	benign	Von Hippel-Lindau syndrome	2024-06-25	reviewed by expert panel	curation	The variant NM_000551.4(VHL):c.119C>T (p.Pro40Leu) is a missense variant predicted to cause substitution of Proline by Leucine. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0006831 (71/ 84504 from South Asian 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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199012	SCV000254648	likely benign	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565432	SCV000664620	likely benign	Hereditary cancer-predisposing syndrome	2022-05-02	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.
Counsyl	RCV000662921	SCV000785868	uncertain significance	Von Hippel-Lindau syndrome	2017-12-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001588971	SCV001822387	likely benign	not provided	2020-11-25	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously reported as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28188106, 24728327, 24727139)
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153403	SCV003843386	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001588971	SCV004237520	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing
ITMI	RCV000122259	SCV000086483	not provided	not specified	2013-09-19	no assertion provided	reference population