ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.373C>T (p.His125Tyr) (rs375401722)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000479517 SCV000892671 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000479517 SCV000565759 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing This variant is denoted VHL c.373C>T at the cDNA level, p.His125Tyr (H125Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). VHL His125Tyr was observed in a patient with a paraganglioma (Persu 2012). VHL His125Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL His125Tyr occurs at a position that is not conserved and is located in the nuclear export region of the Beta-domain and the region involved in binding to the CCT complex (Yuen 2009, 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 His125Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000708764 SCV000822211 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000462284 SCV000553399 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-05-22 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 125 of the VHL protein (p.His125Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs375401722, ExAC 0.003%). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 411970). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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