Submissions for variant NM_000551.4(VHL):c.338G>C (p.Arg113Pro)

gnomAD frequency: 0.00001  dbSNP: rs767062290

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467414	SCV000553416	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 113 of the VHL protein (p.Arg113Pro). This variant is present in population databases (rs767062290, gnomAD 0.001%). 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: 411987). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics	RCV002451138	SCV002617197	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-29	criteria provided, single submitter	clinical testing	The p.R113P variant (also known as c.338G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 338. The arginine at codon 113 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230506	SCV003929064	uncertain significance	not specified	2023-04-18	criteria provided, single submitter	clinical testing	Variant summary: VHL c.338G>C (p.Arg113Pro) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, as the variant is located in the exonic-splice region, 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.6e-06 in 219392 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.338G>C in individuals affected with Von Hippel-Lindau Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004001992	SCV004821660	uncertain significance	Von Hippel-Lindau syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 113 of the VHL protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 1/219392 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.