Submissions for variant NM_000020.3(ACVRL1):c.967A>G (p.Lys323Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002386985	SCV002694229	uncertain significance	Cardiovascular phenotype	2015-12-24	criteria provided, single submitter	clinical testing	The p.K323E variant (also known as c.967A>G), located in coding exon 6 of the ACVRL1 gene, results from an A to G substitution at nucleotide position 967. The lysine at codon 323 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003509746	SCV004319745	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 323 of the ACVRL1 protein (p.Lys323Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 1767756). 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 with a positive predictive value of 95%. This variant disrupts the p.Lys323 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.