ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.145G>T (p.Val49Phe) (rs1252348200)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693521 SCV000821392 pathogenic Hereditary hemorrhagic telangiectasia 2019-08-23 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 49 of the ENG protein (p.Val49Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hereditary hemorrhagic telangiectasia (PMID: 15024723, 17786384, 21158752, 22991266). Experimental studies have shown that this missense change leads to a defect in ENG protein trafficking in vitro (PMID: 22022569). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287705 SCV001474419 pathogenic Hereditary hemorrhagic telangiectasia type 1 2020-08-04 criteria provided, single submitter clinical testing The ENG c.145G>T; p.Val49Phe variant 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 absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 49 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with these predictions, 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. 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. 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.

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