Submissions for variant NM_000551.4(VHL):c.334T>C (p.Tyr112His)

dbSNP: rs104893824

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000698407	SCV000827068	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 112 of the VHL protein (p.Tyr112His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pheochromocytoma in two families and has been found in an independent family affected with the same condition (PMID: 7728151, 8863170, 21204227). It has also been observed to segregate with disease in related individuals. This variant is also known as c.547T>C, p.Y111H. ClinVar contains an entry for this variant (Variation ID: 2222). 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 expected to disrupt VHL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 15574766, 19030229, 24002598). This variant disrupts the p.Tyr112 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10533030, 11331613, 19602254). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000002308	SCV000897805	pathogenic	Von Hippel-Lindau syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002308	SCV000918341	pathogenic	Von Hippel-Lindau syndrome	2018-09-28	criteria provided, single submitter	clinical testing	Variant summary: VHL c.334T>C (p.Tyr112His) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 217656 control chromosomes. c.334T>C has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome including a large kindred comprised of 107 people with or at-risk for VHL, of whom 49 have been diagnosed and 35/49 (71%) are clinically affected (Nielsen_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002321468	SCV002606729	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-01	criteria provided, single submitter	clinical testing	The p.Y112H pathogenic mutation (also known as c.334T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 334. The tyrosine at codon 112 is replaced by histidine, an amino acid with similar properties. This variant has been associated with Type 2A VHL and reported to segregate with pheochromocytoma in two large families and has been found in another independent family affected with pheochromocytoma and angiomas (Tisherman SE et al. Arch Intern Med, 1993 Nov;153:2550-6; Chen F et al. Hum Mutat, 1995;5:66-75; Chen F et al. J Med Genet, 1996 Aug;33:716-7; Nielsen SM et al. Am J Med Genet A, 2011 Jan;155A:168-73). Experimental studies have shown that this alteration results in an intermediate degree of HIF regulation in VHL null murine embryonic stem cell expression system and also leads to an increased microvessel density in a mouse model for teratoma analysis (Rathmell WK et al. Cancer Res, 2004 Dec;64:8595-603; Hacker KE et al. PLoS One, 2008 Nov;3:e3801). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003407257	SCV004109013	pathogenic	VHL-related disorder	2023-05-05	criteria provided, single submitter	clinical testing	The VHL c.334T>C variant is predicted to result in the amino acid substitution p.Tyr112His. This variant also described using legacy nomenclature as c.547T>C, p.Y111H; has been well-documented to be pathogenic for Type 2A von Hippel-Lindau disease (VHL) with pheochromocytoma (Chen et al. 1995. PubMed ID: 7728151; Zbar et al. 1996. PubMed ID: 8956040; Nielsen et al. 2011. PubMed ID: 21204227). Functional studies showed that this variant affects VHL function (Rathmell et al. 2004. PubMed ID: 15574766; Hacker et al. 2008. PubMed ID: 19030229). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000002308	SCV000022466	pathogenic	Von Hippel-Lindau syndrome	1996-01-01	no assertion criteria provided	literature only