Submissions for variant NM_000551.4(VHL):c.14C>T (p.Ala5Val)

gnomAD frequency: 0.00002  dbSNP: rs755333116

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195431	SCV000254649	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5 of the VHL protein (p.Ala5Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 216476). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000409910	SCV000489266	uncertain significance	Von Hippel-Lindau syndrome	2016-09-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492641	SCV000580990	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	The p.A5V variant (also known as c.14C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 14. The alanine at codon 5 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001582695	SCV001818547	uncertain significance	not provided	2021-07-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Baylor Genetics	RCV003462330	SCV004208744	uncertain significance	Chuvash polycythemia	2023-09-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000409910	SCV004822929	uncertain significance	Von Hippel-Lindau syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 5 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 in individuals affected with VHL-related disorders in the literature. This variant has not been identified 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.