Submissions for variant NM_000020.3(ACVRL1):c.706G>A (p.Glu236Lys)

dbSNP: rs1592223490

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV000814495	SCV004805895	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2024-03-15	reviewed by expert panel	curation	The NM_000020.3: c.706G>A variant in ACVRL1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 236 (p.Glu236Lys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 4 probands with a phenotype consistent of HHT (PS4; PMID: 25970827, ClinVar, Internal lab contributors). The variant has been reported to segregate with HHT in 5 affected members from 1 family, and in 2 affected siblings from a different family (PP1_Strong; PMID: 25970827, personal communication). The computational predictor REVEL gives a score of 0.668, which is above the threshold of greater than or equal to 0.644, evidence that correlates with impact to ACVRL1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for Hereditary Hemorrhagic Telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4, PP1_Strong, PP3 (specification version 1.0.0; 1/04/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814495	SCV000954908	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2020-03-25	criteria provided, single submitter	clinical testing	This variant has been observed in individuals affected with hereditary hemorrhagic telangiectasia (HHT) and observed to segregate with HHT in one family (PMID: 25970827, Invitae). ClinVar contains an entry for this variant (Variation ID: 657805). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 236 of the ACVRL1 protein (p.Glu236Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000814495	SCV001473784	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 2	2019-12-14	criteria provided, single submitter	clinical testing	The ACVRL1 c.706G>A; p.Glu236Lys variant is reported in the literature in at least one family affected with hereditary hemorrhagic telangiectasia (Heimdal 2016). This variant is reported in ClinVar (Variation ID: 657805), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 236 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Glu236Lys variant is uncertain at this time. References: Heimdal K et al. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1. Clin Genet. 2016 Feb;89(2):182-6.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507806	SCV001713599	likely pathogenic	not provided	2021-02-18	criteria provided, single submitter	clinical testing	PS4_moderate, PM2-supporting, PP4, PP3, PS3_supporting, PP1
Ambry Genetics	RCV003307520	SCV003997013	likely pathogenic	Cardiovascular phenotype	2023-05-02	criteria provided, single submitter	clinical testing	The p.E236K variant (also known as c.706G>A), located in coding exon 5 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 706. The glutamic acid at codon 236 is replaced by lysine, an amino acid with similar properties. This alteration has been observed in multiple unrelated individuals with clinical features of hereditary hemorrhagic telangiectasia and co-segregated with disease in other family members (Heimdal K et al. Clin Genet, 2016 Feb;89:182-6; external communication). This amino acid position is completely conserved on sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.