ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.360+1G>A (rs886039505)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255227 SCV000322195 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing The c.360+1 G>A pathogenic variant in the ENG gene has been reported in multiple unrelated patients with HHT across various ethnic backgrounds (Pece et al., 1997; Cymerman et al., 2003; Letteboer et al., 2005; Schulte et al., 2005; Bayrak-Toydemir et al., 2006; Bossler et al., 2006; Olivieri et al., 2007; Kim et al., 2011; Nishida et al., 2012). This variant was identified in a child with HHT who inherited it from her affected mother; subsequent genetic testing of the unaffected maternal grandparents revealed this was a de novo variant in the mother (Cymerman et al., 2003; Mei-Zahav et al., 2006). In addition, Kim et al. (2011) reported that the c.360+1 G>A variant segregated with disease in multiple affected individuals from a Korean family with HHT. Furthermore, this variant has been observed in other unrelated individuals referred for HHT genetic testing at GeneDx. The c.360+1 G>A variant destroys the canonical splice donor site in intron 3 and is predicted to cause abnormal gene splicing. Functional studies demonstrate that c.360+1 G>A leads to in-frame skipping of exon 3 and reduced cell surface endoglin protein, which the authors propose results in transient intracellular expression likely due to protein degradation (Pece et al., 1997). Finally, the c.360+1 G>A variant was not observed in large population cohorts (Lek et al., 2016). In summary, c.360+1 G>A in the ENG gene is interpreted as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255227 SCV000344395 pathogenic not provided 2016-08-11 criteria provided, single submitter clinical testing
Invitae RCV001034674 SCV000629569 pathogenic Hereditary hemorrhagic telangiectasia 2020-05-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the ENG gene. It is expected to disrupt RNA splicing and results in a disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic. This particular variant has been reported in the literature in multiple individuals and families with hemorrhagic telangiectasia (PMID: 9366572, 15880681, 19508727, 21158752, 21967607, 22991266, 25970827). Experimental studies have shown that this splicing change has a deleterious effect on the resulting protein (PMID: 9366572). For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000274164 SCV001441154 pathogenic Hereditary hemorrhagic telangiectasia type 1 2018-01-01 criteria provided, single submitter research PVS1+PM2+PP4
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000274164 SCV001474418 pathogenic Hereditary hemorrhagic telangiectasia type 1 2020-07-31 criteria provided, single submitter clinical testing The ENG c.360+1G>A variant (rs886039505) is reported in the literature in multiple individuals and families with hereditary hemorrhagic telangiectasia (ENG HHT database, Heimdal 2016, Kim 2011, McDonald 2011, Nishida 2012, Pece 1997, Sadick 2009, Schulte 2005). This variant is reported as pathogenic three times in ClinVar (Variation ID: 265370), but is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Functional analysis shows that this variant disrupts the canonical splice donor site in the 5’ end of intron 3 and leads to skipping of exon 3 (Pece 1997). Based on the above information, this variant is considered pathogenic. REFERENCES ENG HHT database: Heimdal K et al. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1. Clin Genet. 2016 Feb;89(2):182-6. Kim M et al. Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2011; 12: 130. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. Nishida T et al. Brain Arteriovenous Malformations associated with Hereditary Hemorrhagic Telangiectasia: Gene-Phenotype Correlations. Am J Med Genet A. 2012 Nov; 0(11): 2829–2834. Pece N et al. Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. J Clin Invest. 1997 Nov 15;100(10):2568-79. Sadick H et al. Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique. BMC Med Genet. 2009; 10: 53. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595.
OMIM RCV000274164 SCV000038431 pathogenic Hereditary hemorrhagic telangiectasia type 1 1997-11-15 no assertion criteria provided literature only

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