ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1313T>C (p.Met438Thr) (rs1555153828)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000640434 SCV000762025 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 438 of the ACVRL1 protein (p.Met438Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15517393, 31327192, Invitae). ClinVar contains an entry for this variant (Variation ID: 533343). 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 disrupts the p.Met438 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 21158752, 28655553), which suggests that this may be a clinically significant amino acid residue. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000640434 SCV001156569 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-11-07 criteria provided, single submitter clinical testing The ACVRL1 c.1313T>C; p.Met438Thr variant is reported in the literature in at least one individual affected with hereditary hemorrhagic telangiectasia (HHT) (Letteboer 2005). This variant is reported in ClinVar (Variation ID: 533343), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 438 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.1313T>G, p.Met438Arg; c.1313T>A, p.Met438Lys) have been reported in individuals with vascular anomalies (Mattassi 2018, McDonald 2011). Based on available information, the p.Met438Thr variant is considered to be likely pathogenic. References: Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. Mattassi R et al. Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management. J Vasc Surg. 2018 Mar;67(3):922-932.e11. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44.

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