ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.125A>C (p.Glu42Ala)

dbSNP: rs1064796244
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485480 SCV000572771 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing This variant is denoted VHL c.125A>C at the cDNA level, p.Glu42Ala (E42A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. VHL Glu42Ala was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Glu42Ala occurs at a position that is not conserved and is located within the 6th repeat of a tandem repeat region (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Glu42Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001851244 SCV002130150 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 42 of the VHL protein (p.Glu42Ala). This variant is not present in population databases (gnomAD no frequency). 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: 423120). 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.
Ambry Genetics RCV002431413 SCV002680491 uncertain significance Hereditary cancer-predisposing syndrome 2024-09-13 criteria provided, single submitter clinical testing The p.E42A variant (also known as c.125A>C), located in coding exon 1 of the VHL gene, results from an A to C substitution at nucleotide position 125. The glutamic acid at codon 42 is replaced by alanine, 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 tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002489170 SCV002781988 uncertain significance Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma 2021-07-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV003470583 SCV004208751 uncertain significance Chuvash polycythemia 2023-08-28 criteria provided, single submitter clinical testing

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