Submissions for variant NM_000551.4(VHL):c.292T>C (p.Tyr98His)

gnomAD frequency: 0.00001  dbSNP: rs5030809

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000679029	SCV000203787	pathogenic	not provided	2015-03-23	criteria provided, single submitter	clinical testing
Invitae	RCV000684783	SCV000553393	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-08	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 98 of the VHL protein (p.Tyr98His). This variant is present in population databases (rs5030809, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of VHL-related conditions (PMID: 7728151, 7759077, 10408776, 11483638, 19336503, 19763184, 21204227). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2223). 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: 10878807, 11331612, 11331613, 12510195, 16261165, 23840444, 25371412). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492094	SCV000580959	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-12	criteria provided, single submitter	clinical testing	The p.Y98H pathogenic mutation (also known as c.292T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 292. The tyrosine at codon 98 is replaced by histidine, an amino acid with similar properties. This mutation has been reported in numerous VHL families in the literature (Crossey PA et al. Hum Mol Genet. 1994 Aug;3:1303-8; Neumann HP et al. N Engl J Med. 2002 May;346:1459-66; Gallou C et al. Hum. Mutat. 2004 Sep;24:215-24; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94:1938-44; Erlic Z et al. Endocr Relat Cancer. 2010 Dec;17:875-83; Nielsen SM et al. Am J Med Genet A. 2011 Jan;155A:168-73; Klingler JH et al. J Stroke Cerebrovasc Dis. 2013 May;22:437-43; Huang KL et al. Cell. 2018 04;173:355-370.e14; Liu P et al. Gland Surg, 2019 Aug;8:343-353). In addition, this mutation was shown to disrupt microtubule stabilization in vitro and has been noted to be associated with Type 2A VHL (Hergovich A et al. Nat Cell Biol. 2003;5(1):64-70; Bangiyeva V et al. BMC Cancer. 2009;9:229). Of note, this may be referred to as c.505T>A in some literature. Based on available evidence to date, this alteration is considered to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002309	SCV000697496	pathogenic	Von Hippel-Lindau syndrome	2023-06-21	criteria provided, single submitter	clinical testing	Variant summary: VHL c.292T>C (p.Tyr98His) results in a conservative amino acid change located in the VHL beta/alpha domain (IPR022772) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 223464 control chromosomes in gnomAD. c.292T>C has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome, has been shown to segregate with disease, and has been considered a founder mutation in Black Forest region of Germany (example: Brauch_1995). At least one publication reports experimental evidence evaluating an impact on protein function. One of the most pronounced variant effects results in impaired binding with HIF protein (example: Couve_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 7759077, 25371412). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003891425	SCV000805336	pathogenic	VHL-related disorder	2023-11-22	criteria provided, single submitter	clinical testing	The VHL c.292T>C variant is predicted to result in the amino acid substitution p.Tyr98His. This variant has previously been reported in multiple individuals with pheochromocytoma and Von Hippel-Lindau disease (Crossey et al. 1994. PubMed ID: 7987306, described as 505T>C/169Tyr>His; Boedeker et al. 2009. PubMed ID: 19336503; Gallou et al. 1999. PubMed ID: 10408776; Nielsen et al. 2011. PubMed ID: 21204227). This variant is reported in 3 of ~233,000 alleles in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/103904398/). This variant is interpreted as pathogenic.
Athena Diagnostics	RCV000679029	SCV001146628	pathogenic	not provided	2019-02-15	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease. However, available data are from a single family.
Johns Hopkins Genomics, Johns Hopkins University	RCV000002309	SCV001425361	pathogenic	Von Hippel-Lindau syndrome	2020-03-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679029	SCV002496779	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000002309	SCV002579181	pathogenic	Von Hippel-Lindau syndrome	2022-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679029	SCV002774400	pathogenic	not provided	2019-02-15	criteria provided, single submitter	clinical testing	This variant has been reported as pathogenic in multiple individuals and families with Von Hippel-Lindau disease in the published literature, where it has been shown to segregate with disease (PMIDs: 21204227 (2011), 19763184 (2009), 19336503 (2009), 11709017 (2001), 11483638 (2001), 10567493 (1999), 10408776 (1999), and 7759077 (1995)). Multiple experimental studies indicate that the variant is damaging to VHL protein function (PMIDs: 28643803 (2017), 20855504 (2010), 20388653 (2010), 19620968 (2009), and 16261165 (2006)). Therefore, the variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000002309	SCV003806645	pathogenic	Von Hippel-Lindau syndrome	2023-01-31	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11483638, 7759077, 34416425, 32869749, 31538058]. Functional studies indicate this variant impacts protein function [PMID: 28052007, 19602254, 16261165, 23840444, 11331612]. This variant is expected to disrupt protein structure [internal Myriad data].
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000002309	SCV004847781	pathogenic	Von Hippel-Lindau syndrome	2019-12-03	criteria provided, single submitter	clinical testing	The p.Tyr98His variant in VHL has been reported in >25 individuals with Von Hippel-Lindau disease and segregated with disease in >50 affected individuals from several families, and is considered a founder variant in the Black Forest region in Germany (Bender 2001). It has also been identified in 2/100722 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 2223). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Hoffman 2001, Clifford 2001, Shmueli 2013). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Von Hippel- Lindeau disease. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting, PP3.
OMIM	RCV000002309	SCV000022467	pathogenic	Von Hippel-Lindau syndrome	2001-11-01	no assertion criteria provided	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000002309	SCV000264695	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing
Clinical Genomics Labs, University Health Network	RCV000002309	SCV001950154	pathogenic	Von Hippel-Lindau syndrome	2019-05-24	no assertion criteria provided	clinical testing