Submissions for variant NM_000551.4(VHL):c.245G>T (p.Arg82Leu)

dbSNP: rs794726890

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000631271	SCV000752299	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2019-08-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Arg82Pro) has been reported to segregate with von Hippel-Lindau syndrome in two families (PMID: 12603429, 20447124). Experimental studies have shown that this missense change disrupts the normal function of VHL protein (PMID: 26973240, 11739384, 10823831). This suggests that the arginine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. This variant has been reported to be de novo in an individual affected with bilateral adrenal pheochromocytoma (PMID: 23327821). In addition, this variant has been reported to segregate with bilateral pheochromocytoma in one family (PMID: 23626751). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 82 of the VHL protein (p.Arg82Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553666	SCV001774603	likely pathogenic	Von Hippel-Lindau syndrome	2021-07-08	criteria provided, single submitter	clinical testing	Variant summary: VHL c.245G>T (p.Arg82Leu) results in a non-conservative amino acid change located in the VHL disease tumor suppressor, beta/alpha domain (IPR022772) 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 229092 control chromosomes. c.245G>T has been reported in the literature in the setting of bilateral pheochromocytoma in the absence of other tumors reported in patients with von Hippel-Lindau disease (example, Mary John_2013, Amini_2013) and a in report of custom multigene panel of 17 paraganglioma and pheochromocytoma (PPGL) genes (Ben Amin_2019). The variant segregated with bilateral pheochromocytoma in one family (Mary John_2013) and originated de-novo in the other (Amini_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Although several reports describing an impact of a different missense variant located at this codon, namely p.Arg82Pro as impacting VHL function have been published, supporting the relevance of this Arginine residue. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping clinical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002448934	SCV002732297	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-10	criteria provided, single submitter	clinical testing	The p.R82L variant (also known as c.245G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 245. The arginine at codon 82 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with VHL spectrum tumors, including a proband and two children all with bilateral pheochromocytomas and all positive for this variant (Amini Z et al. J. Pediatr. Endocrinol. Metab., 2013;26:369-72; Krauss T et al. Endocr. Relat. Cancer, 2018 09;25:783-793; Ebenazer A et al. Fam. Cancer, 2013 Sep;12:519-24; John AM et al. PLoS ONE, 2013 Apr;8:e61908; Penitenti F et al. Endocrine, 2021 Oct;74:180-187; Ambry internal data). Based on internal structural analysis, R82L is deleterious (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV001553666	SCV004019579	likely pathogenic	Von Hippel-Lindau syndrome	2023-03-03	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23626751, 30877234, 23327821, 34036514]. This variant is expected to disrupt protein structure [Myriad internal data].