Submissions for variant NM_000020.3(ACVRL1):c.872_873del (p.Arg291fs)

dbSNP: rs1592224087

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799743	SCV000939419	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg291Thrfs*100) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACVRL1-related conditions. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000799743	SCV002506173	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2022-01-10	criteria provided, single submitter	clinical testing	The ACVRL1 c.872_873delGA; p.Arg291ThrfsTer100 variant (rs1592224087), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 645621). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deletion two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic.
Ambry Genetics	RCV002370110	SCV002684173	pathogenic	Cardiovascular phenotype	2023-04-27	criteria provided, single submitter	clinical testing	The c.872_873delGA pathogenic mutation, located in coding exon 6 of the ACVRL1 gene, results from a deletion of two nucleotides between positions 872 and 873, causing a translational frameshift with a predicted alternate stop codon (p.R291Tfs*100). This mutation has been detected in multiple families with clinical features of hereditary hemorrhagic telangiectasia. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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.
Molecular Genetics, Royal Melbourne Hospital	RCV003994122	SCV004812776	pathogenic	Hereditary hemorrhagic telangiectasia	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in ACVRL1 is a frameshift variant predicted to cause a premature stop codon, p.(Arg291Thrfs*100), in biologically relevant exon 8/10 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant is absent from the population database gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the relevant literature in any individuals. This variant has been identified in at least one proband with a clinical diagnosis of hereditary haemorrhagic telangiectasia (Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4_Supporting, PM2_Supporting.