rs863223413
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP4_ModeratePP3PM2_SupportingPS4PP1_StrongPM1PS3_Supporting
This summary comes from the ClinGen Evidence Repository: 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 ≥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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA322708/MONDO:0010880/135
Frequency
Consequence
NM_000020.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ACVRL1 | NM_000020.3 | c.998G>T | p.Ser333Ile | missense_variant | Exon 7 of 10 | ENST00000388922.9 | NP_000011.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:4
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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). -
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The ACVRL1 c.998G>T; p.Ser333Ile variant (rs863223413), is reported in the literature in several families affected with HHT (Abdalla 2000, Berg 1997, Lux 2013, McDonald 2011). This variant is reported as pathogenic in ClinVar (Variation ID: 212802), and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analyses of the variant protein show reduced expression and a dominant-negative effect on the wild-type protein (Abdalla 2000, Gu 2006). The serine at codon 333 is a highly conserved residue in the protein kinase domain, and computational algorithms predict that this variant is deleterious (REVEL: 0.975). Based on available information, the p.Ser333Ile variant is considered to be pathogenic. References: Abdalla SA et al. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum Mol Genet. 2000 May 1;9(8):1227-37. PMID: 10767348. 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. PMID: 9245985. Gu Y et al. Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood. 2006 Mar 1;107(5):1951-4. PMID: 16282348. Lux A et al. HHT diagnosis by Mid-infrared spectroscopy and artificial neural network analysis. Orphanet J Rare Dis. 2013 Jun 27;8:94. PMID: 23805858. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. PMID: 21158752. -
not provided Pathogenic:2
PP1_strong, PP3, PP4, PM2_supporting, PS3_moderate, PS4 -
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) -
Cardiovascular phenotype Pathogenic:1
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. -
Hereditary hemorrhagic telangiectasia Pathogenic:1
Variant summary: ACVRL1 c.998G>T (p.Ser333Ile) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249936 control chromosomes. c.998G>T has been reported in the literature in multiple individuals affected with Hereditary Hemorrhagic Telangiectasia (examples: Abdalla_2003 and McDonald_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12700602, 21158752). ClinVar contains an entry for this variant (Variation ID: 212802). Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at