Variant: NM_000020.3(ACVRL1):c.1232G>A (p.Arg411Gln)

CA119395

8243 (ClinVar)

Gene: ACVRL1

Condition: telangiectasia, hereditary hemorrhagic, type 2

Inheritance Mode: Autosomal dominant inheritance

UUID: ed2b5ccd-ee24-43e2-bed3-c10a3a4e0706

Approved on: 2024-03-15

Published on: 2024-03-15

HGVS expressions

NM_000020.3:c.1232G>A
NM_000020.3(ACVRL1):c.1232G>A (p.Arg411Gln)
NC_000012.12:g.51916219G>A
CM000674.2:g.51916219G>A
NC_000012.11:g.52310003G>A
CM000674.1:g.52310003G>A
NC_000012.10:g.50596270G>A
NG_009549.1:g.13802G>A
ENST00000547400.6:c.962G>A
ENST00000551576.6:c.1232G>A
ENST00000552678.2:c.1232G>A
ENST00000388922.9:c.1232G>A
ENST00000388922.8:c.1232G>A
ENST00000419526.6:c.710G>A
ENST00000547632.1:n.507G>A
ENST00000550683.5:c.1274G>A
ENST00000552678.1:c.237G>A
NM_000020.2:c.1232G>A
NM_001077401.1:c.1232G>A
NM_001077401.2:c.1232G>A

Pathogenic

• Met criteria codes: PP1_Strong PP4_Moderate PM2_Supporting PS4 PP3 PS3_Supporting

Expert Panel

Hereditary Hemorrhagic Telangiectasia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACVRL1 Version 1.0.0

Evidence submitted by expert panel

Hereditary Hemorrhagic Telangiectasia VCEP

The NM_000020.3: c.1232G>A variant in ACVRL1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 411 (p.Arg411Gln). The overall minor allele frequency in gnomAD v2.1.1 is 0.000007980 (2/250642 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 8640225, 31400083, 32300199, 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; PMID: 32300199). The variant has been reported to segregate with HHT in 8 affected family members from one family (PP1_Strong; PMID: 8640225). The computational predictor REVEL gives a score of 0.904, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, binding assays in cell lines showed no BMP9 response indicating that this variant impacts protein function (PS3_Supporting; PMID: 20501893). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PP1_Strong, PP4_Moderate, PM2_Supporting, PP3, PS3_Supporting (specification version 1.0.0; 1/4/2024).

Met criteria codes

• PP1_Strong: The variant has been reported to segregate with HHT in 8 affected family members from one family (PP1_Strong; PMID: 8640225).
• PP4_Moderate: 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; PMID: 32300199).
• PM2_Supporting: The overall minor allele frequency in gnomAD v2.1.1 is 0.000007980 (2/250642 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PS4: This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 8640225, 31400083, 32300199, Internal lab contributors).
• PP3: The computational predictor REVEL gives a score of 0.904, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3).
• PS3_Supporting: Binding assays in cell lines showed no BMP9 response indicating that this variant impacts protein function (PS3_Supporting; PMID: 20501893).