ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.662T>C (p.Leu221Pro) (rs1554810378)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000500817 SCV000594549 pathogenic Hereditary hemorrhagic telangiectasia type 1 2017-04-15 criteria provided, single submitter clinical testing
Invitae RCV000633131 SCV000754345 pathogenic Hereditary hemorrhagic telangiectasia 2019-08-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 221 of the ENG protein (p.Leu221Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with hereditary hemorrhagic telangiectasia (PMID: 10545596, 22991266, 15880681, 15712270, 11440987, 21158752, 16690726, 18498373). Experimental studies have shown that this missense change reduced expression of endonglin (PMID: 10545596). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000500817 SCV001474417 pathogenic Hereditary hemorrhagic telangiectasia type 1 2020-04-28 criteria provided, single submitter clinical testing The ENG c.662T>C; p.Leu221Pro variant is reported in multiple unrelated individuals and families with HHT (Gedge 2007, Kuehl 2005, Pece-Barbara 1999, Nishida 2012, Schulte 2005), and is classified as pathogenic in the ClinVar database (Variation ID: 435060). Experimental studies demonstrated that the variant causes reduced endoglin expression (Pece-Barbara 1999). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 221 is not highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. Kuehl HK et al. Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations. Hum Mutat. 2005 Mar;25(3):320. Pece-Barbara N et al. Expression analysis of four endoglin missense mutations suggests that haploinsufficiency is the predominant mechanism for hereditary hemorrhagic telangiectasia type 1. Hum Mol Genet. 1999 Nov;8(12):2171-81. 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. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595.
GeneDx RCV001565138 SCV001788422 pathogenic not provided 2019-06-28 no assertion criteria provided clinical testing Published functional studies demonstrate L221P has a damaging effect by leading to protein misfolding and minimal protein expression at the cell surface (Pece-Barbara et al., 1999); Reported in ClinVar as pathogenic but additional evidence is not available (ClinVar Variant ID# 435060; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32300199, 11440987, 18498373, 21158752, 22991266, 17384219, 15880681, 10545596, 15712270, 16690726)

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