Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001036645 | SCV001200020 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2023-06-27 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 6 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). 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 disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 835700). Disruption of this splice site has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). |
Ambry Genetics | RCV002400218 | SCV002669240 | pathogenic | Cardiovascular phenotype | 2021-04-01 | criteria provided, single submitter | clinical testing | The c.772+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 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 may weaken the native splice donor 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 missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been detected in individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Mayo Clinic Laboratories, |
RCV003480911 | SCV004226863 | pathogenic | not provided | 2022-12-15 | criteria provided, single submitter | clinical testing | PM2_supporting, PS4_moderate, PVS1_strong |
ARUP Laboratories, |
RCV001036645 | SCV004565028 | pathogenic | Telangiectasia, hereditary hemorrhagic, type 2 | 2023-04-10 | criteria provided, single submitter | clinical testing | The ACVRL1 c.772+1G>C variant (rs1940785759), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 835700). Different variants at this splice junction (c.773-1G>A, c.773-2A>C, c.773-2A>G) have been seen in individuals suspected of having HHT (ARUP internal data, Lesca 2004). The c.772+1G>C variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 6, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. PMID: 15024723. |