ClinVar Genomic variation as it relates to human health

The ENG c.145G>T; p.Val49Phe variant (rs1252348200) is reported in the literature in several individuals with a diagnosis or symptoms of hereditary haemorrhagic telangiectasia (HHT) (Lesca 2004, Nishida 2012). In testing performed at ARUP Laboratories, this variant has also been observed in individuals with symptoms of HHT and has been found to segregate with disease in at least one family. This variant is also reported in ClinVar (Variation ID: 572196), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 49 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.375). However, functional studies suggest the p.Val49Phe variant is mislocalized to the endoplasmic reticulum and fails to traffic to the plasma membrane like wildtype protein (Ali 2011). Based on available information, this variant is considered to be pathogenic. References: Ali BR et al. Endoplasmic reticulum quality control is involved in the mechanism of endoglin-mediated hereditary haemorrhagic telangiectasia. PLoS One. 2011;6(10):e26206. PMID: 22022569. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. PMID: 15024723. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. PMID: 22991266.

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; This variant is associated with the following publications: (PMID: 22991266, 32300199, 15879500, 15024723, 20067780, 17786384, 21158752, 22022569)

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ENG function (PMID: 22022569). 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 ENG protein function. ClinVar contains an entry for this variant (Variation ID: 572196). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 15024723, 17786384, 21158752, 22991266). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 49 of the ENG protein (p.Val49Phe).

The p.V49F pathogenic mutation (also known as c.145G>T), located in coding exon 2 of the ENG gene, results from a G to T substitution at nucleotide position 145. The valine at codon 49 is replaced by phenylalanine, an amino acid with highly similar properties. This mutation has been reported in multiple unrelated individuals with clinical diagnosis of hereditary hemorrhagic telangiectasia (Lesca G et al. Hum. Mutat., 2004 Apr;23:289-99; Olivieri C et al. J. Hum. Genet., 2007 Sep;52:820-9; McDonald J et al. Clin. Genet., 2011 Apr;79:335-44; Nishida T et al. Am. J. Med. Genet. A, 2012 Nov;158A:2829-34). When expressed in cell lines, the V49F mutant protein was retained in endoplasmic reticulum and failed to reach plasma membrane (Ali BR et al. PLoS ONE, 2011 Oct;6:e26206). This variant was not reported in population-based 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.

PP1, PP4, PM2, PS3, PS4