Submissions for variant NM_000020.3(ACVRL1):c.1336C>T (p.Gln446Ter)

dbSNP: rs1064794217

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479233	SCV000568238	likely pathogenic	not provided	2017-03-21	criteria provided, single submitter	clinical testing	The Q446X variant in the ACVRL1 gene has been reported in one individual with HHT (McDonald et al., 2011). The Q446X variant is predicted to cause loss of normal protein function by protein truncation, as the last 58 amino acid residues of the protein are lost. Other nonsense variants in the ACVRL1 gene, including several downstream, have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014). Furthermore, the Q446X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Nevertheless, this variant lacks a sufficient number of probands, segregation data, and functional studies to be able to definitively determine is pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531463	SCV000639392	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2024-06-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln446*) in the ACVRL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the ACVRL1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hemorrhagic telangiectasia (PMID: 21158752). ClinVar contains an entry for this variant (Variation ID: 419979). This variant disrupts a region of the ACVRL1 protein in which other variant(s) (p.Arg479*) have been determined to be pathogenic (PMID: 15024723, 15065824, 15517393, 15712271, 16429404, 16540754, 18673552, 21158752, 23722869). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.