rs1555152520
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000020.3(ACVRL1):c.265T>C(p.Cys89Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C89F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000020.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACVRL1 | NM_000020.3 | c.265T>C | p.Cys89Arg | missense_variant | 3/10 | ENST00000388922.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACVRL1 | ENST00000388922.9 | c.265T>C | p.Cys89Arg | missense_variant | 3/10 | 1 | NM_000020.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 16, 2016 | - - |
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2021 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function. This variant has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 439381). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 89 of the ACVRL1 protein (p.Cys89Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant affects a cysteine residue located within the ACVRL1 protein ectodomain. Cysteine residues in this domain of ACVRL1 are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 22028876, 22718755, 22799562). In addition, missense substitutions within the ACVRL1 ectodomain affecting cysteine residues are overrepresented in patients with HHT (PMID: 20501893, 26176610 and www.hhtmutation.org). This variant disrupts the p.Cys89 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2021 | The p.C89R variant (also known as c.265T>C), located in coding exon 2 of the ACVRL1 gene, results from a T to C substitution at nucleotide position 265. The cysteine at codon 89 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT), as well as in individuals with concerns for HHT (McDonald J et al. Genet Med, 2020 07;22:1201-1205; Major T et al. J Clin Med, 2021 Aug;10:[ePub ahead of print]; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at