ClinVar Genomic variation as it relates to human health

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 305 of the ACVRL1 protein (p.Ser305Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 17384219, 29171923; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 439382). 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. This variant disrupts the p.Ser305 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 15712271, 17384219, 29171923; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

The ACVRL1 c.914C>T; p.Ser305Phe variant is reported in the literature in individuals affected with symptoms of HHT (Gedge 2007, Saliou 2017), and has been identified by our laboratory in several other affected individuals. This variant is also reported in ClinVar (Variation ID: 439382). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The serine at codon 305 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, two other variants at this codon (Ser305Pro, Ser305Tyr) have been reported in association with HHT or pulmonary arterial hypertension (Abdalla 2005, Yang 2018), giving further support for the importance of this residue. 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. 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. Saliou G et al. Clinical and genetic findings in children with central nervous system arteriovenous fistulas. Ann Neurol. 2017 Dec;82(6):972-980. Yang H et al. Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. Respir Res. 2018 May 9;19(1):87.

The p.S305F likely pathogenic variant (also known as c.914C>T), located in coding exon 6 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 914. The serine at codon 305 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been detected in individuals with a diagnosis of hereditary hemorrhagic telangiectasia (HHT) meeting Curacao criteria (Gedge F, J Mol Diagn. 2007; 9(2):258-65; McDonald J et al. Genet Med, 2020 Jul;22:1201-1205; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved on sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

The ACVRL1 c.914C>T variant is predicted to result in the amino acid substitution p.Ser305Phe. This variant was reported in an individual with an arteriovenous fistula (Supplemental Table 1 in Saliou et al 2017. PubMed ID: 29171923) and in individuals with hereditary hemorrhagic telangiectasia (HHT) (Table S1 in McDonald J et al 2020. PubMed ID: 32300199; Gedge et al. 2007. PubMed ID: 17384219). This variant has not been reported in a large population database, indicating this variant is rare. Of note, other variants impacting the same amino acid (p.Ser305Pro and p.Ser305Tyr) have also been reported in individuals with ACVRL1-related disease (Abdalla et al. 2005. PubMed ID: 15712271; Table S2 in Yang et al. 2018. PubMed ID: 29743074). Based on this evidence, we interpret the c.914C>T (p.Ser305Phe) variant as pathogenic.