ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.1132C>T (p.Pro378Ser) (rs959973779)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001393 SCV001158599 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-08-10 criteria provided, single submitter clinical testing The ACVRL1 c.1132C>T; p.Pro378Ser variant (rs959973779), is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT) (Alaa 2015, Komiyama 2014, McDonald 2011, Richards-Yutz 2010). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1133C>A, p.Pro378His) has been reported as a de novo variant in a family with HHT (Abdalla 2005). The proline at codon 378 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Furthermore, codon 378 is located in the kinase subdomain VIII, which is critical for substrate recognition (Abdalla 2005, Ricard 2010), and multiple other variants in this domain are considered pathogenic in ClinVar. Based on available information, the p.Pro378Ser variant is considered to be likely pathogenic. References: Abdalla SA et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005 Mar;25(3):320-1. Alaa El Din F et al. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PLoS One. 2015 Jul 15;10(7):e0132111. Komiyama M et al. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet. 2014 Jan;59(1):37-41. 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. Ricard N et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010 Sep 2;116(9):1604-12. Richards-Yutz J et al. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet. 2010 Jul;128(1):61-77.
Invitae RCV001001393 SCV001198087 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2019-07-15 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 378 of the ACVRL1 protein (p.Pro378Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 20414677, 26176610, 21158752, 24196379, Invitae). This variant has been reported to affect ACVRL1 protein function (PMID: 26176610). This variant disrupts the p.Pro378 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 15712271, 12114496), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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