Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000795117 | SCV000934559 | pathogenic | Hereditary hemorrhagic telangiectasia | 2018-12-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 29171923). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in an individual with clinical features of hereditary hemorrhagic telangiectasia (HHT) (PMID: 29171923). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 175 of the ENG protein (p.Ala175Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant also falls at the last nucleotide of exon 4 of the ENG coding sequence, which is part of the consensus splice site for this exon. |
| ARUP Laboratories, |
RCV001002467 | SCV001160413 | likely pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | 2019-03-27 | criteria provided, single submitter | clinical testing | The ENG c.523G>T; p.Ala175Ser variant is reported in the literature in an individual with HHT (Saliou 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. It is located in the last nucleotide of exon 4 and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by significantly weakening the nearby canonical donor splice site. This variant, along with two other variants at this nucleotide (c.523G>C; c.523G>A) are reported in individuals with HHT, and functional analyses of the variant proteins show skipping of exon 4 leading to no detectable protein (Bossler 2006, Cymerman 2003, Saliou 2017). Based on available information, the c.523G>T; p.Ala175Ser variant is considered to be likely pathogenic. REFERENCES Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 Jul;27(7):667-75. Cymerman U et al. Characterization of 17 novel endoglin mutations associated with hereditary hemorrhagic telangiectasia. Hum Mutat. 2003 May;21(5):482-92. Saliou G et al. Clinical and genetic findings in children with central nervous system arteriovenous fistulas. Ann Neurol. 2017 Dec;82(6):972-980. |
| NIHR Bioresource Rare Diseases, |
RCV001002467 | SCV001441164 | likely pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | 2018-01-01 | criteria provided, single submitter | research | PM2+PP3+PP4 |