ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.427G>C (p.Asp143His) (rs372757722)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226491 SCV000285497 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 143 of the VHL protein (p.Asp143His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs372757722, ExAC 0.01%). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 238108). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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 RCV000492555 SCV000580961 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-28 criteria provided, single submitter clinical testing The p.D143H variant (also known as c.427G>C), located in coding exon 2 of the VHL gene, results from a G to C substitution at nucleotide position 427. The aspartic acid at codon 143 is replaced by histidine, an amino acid with some similar properties. This variant was previously reported in the SNPDatabase as rs372757722. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 12000alleles tested) in our clinical cohort.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.

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