rs863223413
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000020.3(ACVRL1):c.998G>T(p.Ser333Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S333C) 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.998G>T | p.Ser333Ile | missense_variant | 7/10 | ENST00000388922.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACVRL1 | ENST00000388922.9 | c.998G>T | p.Ser333Ile | missense_variant | 7/10 | 1 | NM_000020.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 333 of the ACVRL1 protein (p.Ser333Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemmorhagic telangiectasia (PMID: 9245985, 10767348, 12843319, 21158752). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 212802). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 16282348). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen | Mar 15, 2024 | The NM_000020.3: c.998G>T variant in ACVRL1 is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 333 (p.Ser333Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent of HHT (PS4; Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with disease in a large HHT family (PP1_Strong; Internal lab contributors). This variant resides within a region, Arg329-Asn335 (catalytic loop), of ACVRL1 that is defined as a critical functional domain/residue by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM1). The computational predictor REVEL gives a score of 0.975, which is above the threshold of greater than or equal to 0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, western blot in HEK293T, COS7 and Hep3B mutant cells showed reduced surface expression of the variant protein and dominant-negative effect. Moreover, the variant induces embryonic dorsalization indicating that this variant impacts protein function (PS3_Supporting; PMID: 16282348). In summary, this variant meets the criteria to be classified as pathogenic for Hereditary Hemorrhagic Telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM1, PM2_Supporting, PS4, PS3_Supporting, PP1_Strong, PP3, PP4_Moderate (specification version 1.0.0; 1/04/2024). - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 22, 2021 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies in HeLa cells showed intracellular localization and co-localized to the endoplasmic reticulum as opposed to wild-type, and the variant appears to function as a trafficking defect (Harrison et al., 2003; Gu et al., 2006).; This variant is associated with the following publications: (PMID: 10767348, 29398197, 9245985, 15266205, 12843319, 23805858, 32300199, 16282348, 12700602, 29483005, 21158752, 14684682, 10946360) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 01, 2022 | PP1_strong, PP3, PP4, PM2_supporting, PS3_moderate, PS4 - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 10, 2017 | The p.S333I pathogenic mutation (also known as c.998G>T), located in coding exon 6 of the ACVRL1 gene, results from a G to T substitution at nucleotide position 998. The serine at codon 333 is replaced by isoleucine, an amino acid with dissimilar properties. This mutation has been identified in several individuals with HHT, including multiple affected generations of a large family (Berg JN et al. Am. J. Hum. Genet., 1997 Jul;61:60-7; McDonald JE et al. Am. J. Med. Genet., 2000 Aug;93:320-7; Lux A et al. Orphanet J Rare Dis, 2013 Jun;8:94). Functional studies demonstrated this mutation had a dominant-negative effect on the normal protein and resulted in reduced protein expression on the cell surface (Gu Y et al. Blood, 2006 Mar;107:1951-4). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at