Submissions for variant NM_000551.4(VHL):c.556G>A (p.Glu186Lys)

gnomAD frequency: 0.00004  dbSNP: rs367545984

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589801	SCV000292944	uncertain significance	not provided	2024-07-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as c.769G>A, p.E257K; This variant is associated with the following publications: (PMID: 14722919, 8956040, 18836774, 10408776, 9681856, 25637381, 25078357, 20151405, 9829911, 7728151, 28753842, 33102977, Dwivedi2022[Article])
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589801	SCV000697526	uncertain significance	not provided	2016-02-04	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a conserved nucleotide and result in replacement of a medium size and acidic Glutamic acid (E) with a large size and basic Lysine (K). 3/4 in silico tools predict the variant to be disease causing. It was observed in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.003% which exceeds the maximal expected allele frequency of a disease causing VHL variant (0.002). However, the variant was identified in only 2 individuals; therefore the significance of these observations is uncertain. The variant was reported in a Korean family in which the variant carriers presented with Angioma, hemangioblastoma of the brain and renal cell carcinoma (Chen_HumMutat_1995). Additional patients with Type I disease were also reported to carry the variants, however these reports lack information about the prevalence of the variant in healthy individuals, therefore association between the variant and the disease remains uncertain (Stolle_HumMutat_1998, Hwang_JHG_2014, Zbar_HumMutat_1996). HGMD lists variant affecting the same codon c.556G>G (p.E186X) and variants in the close proximity of the variant of interest c.555C>A and c.555C>G (p.Y185X) indicating the variant to be located in a mutational hotspot and suggesting pathogenicity. However, a clinical laboratory classify variant as Uncertain via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant is classified as VUS-possibly pathogenic until more information becomes available.
PreventionGenetics, part of Exact Sciences	RCV000589801	SCV000805357	uncertain significance	not provided	2017-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698671	SCV000827351	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 186 of the VHL protein (p.Glu186Lys). This variant is present in population databases (rs367545984, gnomAD 0.01%). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 25078357). This variant is also known as 769G>T(p.Glu186Lys). ClinVar contains an entry for this variant (Variation ID: 161403). 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%. 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.
Mendelics	RCV000148924	SCV001136314	uncertain significance	Von Hippel-Lindau syndrome	2023-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024290	SCV001186275	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-20	criteria provided, single submitter	clinical testing	The p.E186K variant (also known as c.556G>A), located in coding exon 3 of the VHL gene, results from a G to A substitution at nucleotide position 556. The glutamic acid at codon 186 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in a von Hippel-Lindau (VHL) family affected with retinal angiomas, CNS hemangioblastoma, and renal cell cancer but not pheochromocytomas (Chen F et al. Hum Mutat. 1995;5(1):66-75). This alteration has also been observed in an exome cohort in an unaffected individual (Amendola LM et al. Genome Res. 2015 Mar;25(3):305-15). Of note, this alteration is also known as 769G>A in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Revvity Omics, Revvity	RCV000589801	SCV003820401	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467207	SCV004206459	uncertain significance	Chuvash polycythemia	2024-02-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025228	SCV005658815	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2024-05-30	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148924	SCV000190681	uncertain significance	Von Hippel-Lindau syndrome	2014-06-01	no assertion criteria provided	research