Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000020.3(ACVRL1):c.1468C>T (p.Gln490Ter)

CA384906013

426040 (ClinVar)

Gene: ACVRL1
Condition: telangiectasia, hereditary hemorrhagic, type 2
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8ebf9f7a-0a8a-4ed2-924e-83f8991523cc

HGVS expressions

NM_000020.3:c.1468C>T
NM_000020.3(ACVRL1):c.1468C>T (p.Gln490Ter)
NC_000012.12:g.51920849C>T
CM000674.2:g.51920849C>T
NC_000012.11:g.52314633C>T
CM000674.1:g.52314633C>T
NC_000012.10:g.50600900C>T
NG_009549.1:g.18432C>T
ENST00000547400.6:c.1198C>T
ENST00000551576.6:c.1468C>T
ENST00000388922.9:c.1468C>T
ENST00000388922.8:c.1468C>T
ENST00000419526.6:c.946C>T
ENST00000550683.5:c.1510C>T
NM_000020.2:c.1468C>T
NM_001077401.1:c.1468C>T
NM_001077401.2:c.1468C>T

Pathogenic

Met criteria codes 4
PP1_Strong PS4 PM2_Supporting PVS1_Strong

Evidence Links 0

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hereditary Hemorrhagic Telangiectasia VCEP
The NM_000020.3: c.1468C>T (p.Gln490Ter) variant in ACVRL1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense medicated decay, however it is a truncation of a functionally important region (removes amino acids 490-503) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 15879500, 16829353, 20301525). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID: 16829353, 16540754, 32573726, 11484689, Internal lab contributors). The variant has been reported to segregate with HHT in several affected family members from two large families (PP1_Strong; PMID: 16829353, 11484689). 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: PVS1_Strong, PM2_Supporting, PS4, PP1_Strong (specification version 1.0.0; 1/4/2024).
Met criteria codes
PP1_Strong
The variant has been reported to segregate with HHT in several affected family members from two large families (PP1_Strong; PMID: 16829353, 11484689).
PS4
This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID: 16829353, 16540754, 32573726, 11484689, Internal lab contributors).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PVS1_Strong
The NM_000020.3: c.1468C>T (p.Gln490Ter) variant in ACVRL1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense medicated decay, however it is a truncation of a functionally important region (removes amino acids 490-503) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 15879500, 16829353, 20301525).
Approved on: 2024-03-15
Published on: 2024-03-15
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