Submissions for variant NM_000551.4(VHL):c.383T>C (p.Leu128Pro)

dbSNP: rs2125128327

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001577269	SCV001804620	likely pathogenic	not provided	2019-10-02	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); Observed in individuals with phenotypes consistent with pathogenic variants in VHL referred for genetic testing at GeneDx and in published literature (Cho 2009, Park 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19270817, 27530247, 27527340, 25562111)
Ambry Genetics	RCV002359188	SCV002623574	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-27	criteria provided, single submitter	clinical testing	The p.L128P pathogenic mutation (also known as c.383T>C), located in coding exon 2 of the VHL gene, results from a T to C substitution at nucleotide position 383. The leucine at codon 128 is replaced by proline, an amino acid with similar properties. This alteration has been detected in individuals meeting clinical criteria for von Hippel-Lindau disease (Cho HJ et al. J. Korean Med. Sci. 2009 Feb;24:77-83; Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Testa A et al. J. Am. Chem. Soc. 2018 07;140:9299-9313). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003316842	SCV004019860	likely pathogenic	Von Hippel-Lindau syndrome	2023-04-04	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: 25078357, 25562111, 25081542]. This variant is expected to disrupt protein structure [Myriad internal data].
Labcorp Genetics (formerly Invitae), Labcorp	RCV003771754	SCV004569509	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-07-20	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu128 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8956040, 9681856; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1208816). This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (PMID: 19270817; Invitae). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 128 of the VHL protein (p.Leu128Pro).