Submissions for variant NM_000020.3(ACVRL1):c.1049-1G>A

dbSNP: rs1060503242

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457633	SCV000552409	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the ACVRL1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 20414677; internal data database, internal datadatabase). ClinVar contains an entry for this variant (Variation ID: 411308). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics	RCV002402291	SCV002709186	likely pathogenic	Cardiovascular phenotype	2024-08-30	criteria provided, single submitter	clinical testing	The c.1049-1G>A intronic variant results from a G to A substitution one nucleotide before coding exon 7 of the ACVRL1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been detected in an individual with hereditary hemorrhagic telangiectasia (HHT), and co-occurred with ACVRL1 p.E281* in an individual with HHT (Richards-Yutz J et al. Hum Genet, 2010 Jul;128:61-77; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV002523350	SCV003194939	likely pathogenic	not provided	2023-01-23	criteria provided, single submitter	clinical testing	Identified in individuals with HHT referred for genetic testing at GeneDx and in published literature; these individuals also harbor a second ACVRL1 variant, p.(E281X), though it is unknown if they are present on the same allele or opposite alleles (Richards-Yutz et al., 2010); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20414677)
PreventionGenetics, part of Exact Sciences	RCV004722792	SCV005339279	pathogenic	ACVRL1-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The ACVRL1 c.1049-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant, along with the ACVRL1 c.841G>T (p.Glu281*) variant, was reported in an individual with hereditary hemorrhagic telangiectasia (Richards-Yutz et al. 2010. PubMed ID: 20414677). It was suggested that the c.841G>T and c.1049-1G>A variants were likely on the same allele; however, no additional studies were conducted to determine phase. This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in ACVRL1 are expected to be pathogenic. This variant is interpreted as pathogenic.