rs1555153131
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000020.3(ACVRL1):c.924C>A(p.Cys308*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000020.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACVRL1 | NM_000020.3 | c.924C>A | p.Cys308* | stop_gained | 7/10 | ENST00000388922.9 | NP_000011.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACVRL1 | ENST00000388922.9 | c.924C>A | p.Cys308* | stop_gained | 7/10 | 1 | NM_000020.3 | ENSP00000373574.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461658Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727136
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 21, 2023 | This sequence change creates a premature translational stop signal (p.Cys308*) 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 premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (HHT) (PMID: 9245985, 16123970). ClinVar contains an entry for this variant (Variation ID: 464771). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 24, 2021 | PVS1, PP1, PM2 - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 29, 2018 | The ACVRL1 c.924C>A; p.Cys308Ter variant is reported in the literature in individuals with HHT (Bayrak-Toydemir 2004, Berg 1997, Lenato 2006, Olivieri 2007), and classified as pathogenic in ClinVar (Variation ID: 464771). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and predicted to result in a truncated protein or mRNA subject to nonsense-medicated decay. Based on available information, this variant is considered pathogenic. REFERENCES Bayrak-Toydemir P et al. Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med. 2004 Jul-Aug;6(4):175-91. Berg JN et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997 Jul;61(1):60-7. Lenato GM et al. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Hum Mutat. 2006 Feb;27(2):213-4. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 01, 2024 | PM2, PS4_moderate, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2024 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published studies in patient cells support this variant results in nonsense mediated decay (PMID: 9245985); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16123970, 16429404, 17786384, 23066781, 33919892, 9245985) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2021 | The p.C308* pathogenic mutation (also known as c.924C>A), located in coding exon 6 of the ACVRL1 gene, results from a C to A substitution at nucleotide position 924. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This mutation has been detected in individuals with hereditary hemorrhagic telangiectasia, including multiple affected relatives from one family (Berg JN et al. Am J Hum Genet, 1997 Jul;61:60-7; Argyriou L et al. Liver Transpl, 2005 Sep;11:1132-5; Olivieri C et al. J Hum Genet, 2007 Sep;52:820-829). In addition, the transcript carrying this mutation could not be detected by RT-PCR using mRNA isolated from peripheral blood leukocytes (Berg JN et al. Am J Hum Genet, 1997 Jul;61:60-7). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at