ClinVar Genomic variation as it relates to human health

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.

For these reasons, this variant has been classified as Pathogenic. 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: 12114496, 15712271), which suggests that this may be a clinically significant amino acid residue. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 378 of the ACVRL1 protein (p.Pro378Ser). Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 26176610). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function. ClinVar contains an entry for this variant (Variation ID: 811496). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 20414677, 21158752, 24196379, 26176610; Invitae).

The p.P378S pathogenic mutation (also known as c.1132C>T), located in coding exon 7 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1132. The proline at codon 378 is replaced by serine, an amino acid with similar properties. This mutation was first reported in an individual with expistaxis, telangiectasia, and a family history of hereditary hemorrhagic telangiectasia (Richards-Yutz J, Hum. Genet. 2010 Jul; 128(1):61-77). In addition, in vitro functional studies demonstrated that the resulting protein is predominantly immature and not localized to the cell surface (Alaa El Din F, PLoS ONE 2015 ; 10(7):e0132111). Based on the available evidence to date, this alteration is classified as a pathogenic mutation.