Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001069205 | SCV001234358 | pathogenic | Hereditary hemorrhagic telangiectasia | 2023-10-12 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Asp491Argfs*10) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 10625079, 15712271). This variant is also known as +A FS at 1471. ClinVar contains an entry for this variant (Variation ID: 862475). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV001585973 | SCV001818272 | pathogenic | not provided | 2022-11-11 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10625079, 11440987, 17384219, 16752392, 15024723, 15712271) |
ARUP Laboratories, |
RCV001803223 | SCV002047887 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | 2020-11-10 | criteria provided, single submitter | clinical testing | The ENG c.1470dupA; p.Asp491ArgfsTer10variant, also known as c.1470_1471insA, is reported in the literature in individuals and families affected with hereditary hemorrhagic telangiectasia (Abdalla 2005, Cymerman 2000, Gedge 2007). This variant is also reported in ClinVar (Variation ID: 862475), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Abdalla SA et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005 Mar;25(3):320-1. Cymerman U et al. Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin. Pediatr Res. 2000 Jan;47(1):24-35. 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. |
Ambry Genetics | RCV002393333 | SCV002697951 | pathogenic | Cardiovascular phenotype | 2017-11-13 | criteria provided, single submitter | clinical testing | The c.1470dupA pathogenic mutation, located in coding exon 12 of the ENG gene, results from a duplication of A at nucleotide at position 1470, causing a translational frameshift with a predicted alternate stop codon (p.D491Rfs*10). This mutation was described in a newborn and his father (who had a clinical diagnosis of hereditary hemorrhagic telangiectasia - HHT), and in both individuals decreased levels of fully processed endoglin were observed (Cymerman U et al, Pediatr. Res. 2000 Jan; 47(1):24-35). This mutation was also detected (referred to as c.1470_1471insA) in one patient of a Japanese kindred with multiple family members affected with HHT (Dakeishi M et al, Hum. Mutat. 2002 Feb; 19(2):140-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
Victorian Clinical Genetics Services, |
RCV001803223 | SCV003921883 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 1 | criteria provided, single submitter | clinical testing | - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). - Variant is absent from gnomAD (both v2 and v3). - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least five individuals with hereditary haemorrhagic telangiectasia (PMID: 12673790, ClinVar). Additional information: - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary haemorrhagic telangiectasia type 1 (HHT; MIM#187300). Loss-of-function variants have been reported, with missense variants shown to have both loss of function and dominant negative effects on protein activity (PMID: 25312062). - This gene is associated with autosomal dominant disease. - This variant is heterozygous. - This variant has been shown to be maternally inherited (by trio analysis). |