Submissions for variant NM_000020.3(ACVRL1):c.1270C>A (p.Pro424Thr)

dbSNP: rs1085307419

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810385	SCV000950581	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2018-07-12	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the p.Pro424 amino acid residue in ACVRL1 have been observed in affected individuals (PMID: 9245985, 18159113, 15712271, 22781769). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 9245985) and pulmonary arterial hypertension (PMID: 18159113, Invitae). ClinVar contains an entry for this variant (Variation ID: 426028). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with threonine at codon 424 of the ACVRL1 protein (p.Pro424Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine.
Rare Disease Genomics Group, St George's University of London	RCV000488652	SCV000576336	pathogenic	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only