Submissions for variant NM_000551.4(VHL):c.25G>A (p.Asp9Asn)

gnomAD frequency: 0.00008  dbSNP: rs587780730

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524493	SCV000166405	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 9 of the VHL protein (p.Asp9Asn). This variant is present in population databases (rs587780730, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 135953). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VHL protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000123104	SCV000488949	uncertain significance	Von Hippel-Lindau syndrome	2016-08-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001657771	SCV001874891	uncertain significance	not provided	2021-08-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as germline pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22825683)
Ambry Genetics	RCV002426672	SCV002743322	likely benign	Hereditary cancer-predisposing syndrome	2021-12-06	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.
Revvity Omics, Revvity	RCV001657771	SCV003820404	uncertain significance	not provided	2022-06-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460872	SCV004208750	uncertain significance	Chuvash polycythemia	2023-08-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123104	SCV004815794	uncertain significance	Von Hippel-Lindau syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 9 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 not been reported as a germline variant in individuals affected with VHL-related disorders in the literature. This variant has been identified in 9/172778 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.