ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.574C>T (p.Pro192Ser) (rs28940300)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236065 SCV000293497 uncertain significance not provided 2016-09-26 criteria provided, single submitter clinical testing This variant is denoted VHL c.574C>T at the cDNA level, p.Pro192Ser (P192S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). This variant was observed in the compound heterozygous state with another missense variant in VHL in an individual with polycythemia (Pastore 2003), but was also identified in this patient's unaffected father and brother. VHL Pro192Ser was not observed in approximately 6,500 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 Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Pro192Ser occurs at a position that is conserved across species and is located in the alpha-domain (Yuen 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether VHL Pro192Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000704063 SCV000832996 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 192 of the VHL protein (p.Pro192Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs28940300, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with familial erythrocytosis type 2 (Chuvash polycythemia) (PMID: 12844285). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease.  This variant is also (incorrectly) referred to as p.P192A in the literature (PMID: 12844285). ClinVar contains an entry for this variant (Variation ID: 2234). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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.
OMIM RCV000002322 SCV000022480 pathogenic Erythrocytosis, familial, 2 2003-02-15 no assertion criteria provided literature only

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