Variant: NM_001114753.3(ENG):c.1844C>T (p.Ser615Leu)

CA211415

161229 (ClinVar)

Gene: ENG

Condition: telangiectasia, hereditary hemorrhagic, type 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 6d938fab-e9da-4a5a-b979-c3393ff46cf7

HGVS expressions

NM_001114753.3:c.1844C>T
NM_001114753.3(ENG):c.1844C>T (p.Ser615Leu)
NC_000009.12:g.127815951G>A
CM000671.2:g.127815951G>A
NC_000009.11:g.130578230G>A
CM000671.1:g.130578230G>A
NC_000009.10:g.129618051G>A
NG_009551.1:g.43818C>T
NG_023245.1:g.18077G>A
ENST00000480266.6:c.1298C>T
ENST00000373203.9:c.1844C>T
ENST00000344849.4:c.1844C>T
ENST00000373203.8:c.1844C>T
ENST00000480266.5:c.1298C>T
NM_000118.3:c.1844C>T
NM_001114753.2:c.1844C>T
NM_001278138.1:c.1298C>T
NM_001278138.2:c.1298C>T

Likely Benign

• Met criteria codes: BS1 BP5 BS3_Supporting

• Not Met criteria codes: PP3

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 1.0.0

Evidence submitted by expert panel

Hereditary Hemorrhagic Telangiectasia VCEP

The NM_001114753.3: c.1844C>T variant in ENG is a missense variant predicted to cause substitution of serine by leucine at amino acid 615 (p.Ser615Leu). The filtering allele frequency (the lower threshold of the 95% CI of 285/115780) of the c.1844C>T variant in ENG is 0.002284 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID: 15712270). The computational predictor REVEL gives a score of 0.188, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062, 22022569). In summary, this variant meets the criteria to be classified as likely benign 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: BS1, BP5, BS3_Supporting (specification version 1.0.0; 1/4/2024).

Met criteria codes

• BS1: The filtering allele frequency (the lower threshold of the 95% CI of 285/115780) of the c.1844C>T variant in ENG is 0.002284 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1).
• BP5: This variant has been observed in 1 patient with an alternate molecular basis for disease (also carriers likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID: 15712270).
• BS3_Supporting: Cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062, 22022569).

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.188, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function.

Approved on: 2024-03-15

Published on: 2024-03-15