Variant: NM_001114753.3(ENG):c.1319T>G (p.Val440Gly)

CA374977914

528065 (ClinVar)

Gene: ENG

Condition: telangiectasia, hereditary hemorrhagic, type 1

Inheritance Mode: Autosomal dominant inheritance

UUID: c8cc47f6-4fbb-491f-94e4-4ea9bffa1b71

Approved on: 2024-11-12

Published on: 2025-03-02

HGVS expressions

NM_001114753.3:c.1319T>G
NM_001114753.3(ENG):c.1319T>G (p.Val440Gly)
NC_000009.12:g.127818825A>C
CM000671.2:g.127818825A>C
NC_000009.11:g.130581104A>C
CM000671.1:g.130581104A>C
NC_000009.10:g.129620925A>C
NG_009551.1:g.40944T>G
ENST00000480266.6:c.773T>G
ENST00000373203.9:c.1319T>G
ENST00000344849.4:c.1319T>G
ENST00000373203.8:c.1319T>G
ENST00000480266.5:c.773T>G
NM_000118.3:c.1319T>G
NM_001114753.2:c.1319T>G
NM_001278138.1:c.773T>G
NR_136302.1:n.1568+114A>C
NM_001278138.2:c.773T>G

Likely Pathogenic

• Met criteria codes: PP1_Strong PP4_Moderate PS4_Moderate PM2_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 ENG Version 1.1.0

Evidence submitted by expert panel

Hereditary Hemorrhagic Telangiectasia VCEP

The NM_001114753.3: c.1319T>G variant in ENG is a missense variant predicted to cause substitution of valine by glycine at amino acid 440 (p.Val440Gly). This variant has been reported in more than 2 probands with a phenotype consistent with HHT (PS4_Moderate; 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 Hereditary Hemorrhagic Telangiectasia in 5 affected meioses from 1 family (PP1_Strong; Internal lab contributors). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.385, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as likely 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: PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting (specifications version 1.1.0; 11/12/2024).

Met criteria codes

• PP1_Strong: The variant has been reported to segregate with Hereditary Hemorrhagic Telangiectasia in 5 affected meioses from 1 family (PP1_Strong;Internal lab contributors).
• 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; Internal lab contributors).
• PS4_Moderate: This variant has been reported in more than 2 probands with a phenotype consistent with HHT (PS4_Moderate; Internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v.2.1.1 (PM2_Supporting).