Submissions for variant NM_000020.3(ACVRL1):c.830C>A (p.Thr277Lys)

dbSNP: rs750085854

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001211474	SCV001383015	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2023-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 277 of the ACVRL1 protein (p.Thr277Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 20414677, 25970827; Invitae). ClinVar contains an entry for this variant (Variation ID: 941644). 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. For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001211474	SCV001439468	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2018-01-01	criteria provided, single submitter	research	PM2+PM1+PP4
Mayo Clinic Laboratories, Mayo Clinic	RCV001507807	SCV001713600	pathogenic	not provided	2020-02-12	criteria provided, single submitter	clinical testing	PS4, PM2, PP3, PP1
Ambry Genetics	RCV002429898	SCV002681956	likely pathogenic	Cardiovascular phenotype	2015-09-30	criteria provided, single submitter	clinical testing	The p.T277K variant (also known as c.830C>A), located in coding exon 6 of the ACVRL1 gene, results from a C to A substitution at nucleotide position 830. The threonine at codon 277 is replaced by lysine, an amino acid with similar properties. In Norwegian cohort, this variant was reported to co-segregate with disease and is described as a probable founder mutation in that population (Heimdal K et al. Clin. Genet. 2015). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003393888	SCV004110456	pathogenic	ACVRL1-related condition	2023-01-09	criteria provided, single submitter	clinical testing	The ACVRL1 c.830C>A variant is predicted to result in the amino acid substitution p.Thr277Lys. This variant has been reported in individuals with hereditary hemorrhagic telangiectasia (HHT) (Richards-Yutz et al. 2010. PubMed ID: 20414677; Heimdal et al. 2016. PubMed ID: 25970827; Supplementary Table 1A in Shovlin et al. 2020. PubMed ID: 32573726), and is considered to be a common founder variant in the South-Eastern Norway population (Heimdal et al. 2016. PubMed ID: 25970827). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.