ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.663G>A (p.Trp221Ter)

dbSNP: rs2139070482
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002000185 SCV002228945 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2023-06-23 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 1453216). This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 18673552). This sequence change creates a premature translational stop signal (p.Trp221*) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500).
Ambry Genetics RCV003170168 SCV003899897 pathogenic Cardiovascular phenotype 2023-01-06 criteria provided, single submitter clinical testing The p.W221* pathogenic mutation (also known as c.663G>A), located in coding exon 5 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 663. This changes the amino acid from a tryptophan to a stop codon within coding exon 5. This alteration has been reported in hereditary hemorrhagic telangiectasia (HHT) cohorts and a pulmonary arterial hypertension cohort (Fontalba A et al. BMC Med Genet, 2008 Aug;9:75; McDonald J et al. Clin Genet, 2011 Apr;79:335-44; Song J et al. Clin Sci (Lond), 2016 Nov;130:2043-2052). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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