Submissions for variant NM_000551.4(VHL):c.373C>T (p.His125Tyr)

gnomAD frequency: 0.00001  dbSNP: rs375401722

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462284	SCV000553399	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 125 of the VHL protein (p.His125Tyr). This variant is present in population databases (rs375401722, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 31159747). 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, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx	RCV000479517	SCV000565759	uncertain significance	not provided	2022-09-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with paraganglioma but no other features of von Hippel-Lindau disease, as well as in an individual with a personal/family history of cancer not otherwise specified (Persu et al., 2012; Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 31159747, 24969085, 22566194)
GeneKor MSA	RCV000708764	SCV000822211	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000479517	SCV000892671	uncertain significance	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272247	SCV002556948	uncertain significance	Von Hippel-Lindau syndrome	2021-07-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000708764	SCV002621774	likely benign	Hereditary cancer-predisposing syndrome	2020-05-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002489086	SCV002790478	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2022-05-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV002272247	SCV004827760	uncertain significance	Von Hippel-Lindau syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 125 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual diagnosed with a paraganglioma and no additional features suggestive of von Hippel-Lindau syndrome (PMID: 22566194). This variant has been identified in 3/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.