Submissions for variant NM_001114753.3(ENG):c.1510G>A (p.Val504Met)

gnomAD frequency: 0.00311  dbSNP: rs116330805

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV000273165	SCV004805866	likely benign	Telangiectasia, hereditary hemorrhagic, type 1	2024-03-15	reviewed by expert panel	curation	The NM_001114753.3: c.1510G>A variant in ENG is a missense variant predicted to cause substitution of valine by methionine at amino acid 504 (p.Val504Met). The filtering allele frequency (the lower threshold of the 95% CI of 225/24916) of the c.1510G>A variant in ENG is 0.007757 for African/African American 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 trans with the variant c.23T>C, p.Leu8Pro (PMID: 19767588), which is classified as pathogenic by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, in affected family members with HHT. The phase of the variants was confirmed by parental testing (BP2). The computational predictor REVEL gives a score of 0.239, 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). 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, BP2, BS3_Supporting (specification version 1.0.0; 1/4/2024).
PreventionGenetics, part of Exact Sciences	RCV000246668	SCV000302337	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000246668	SCV000331430	benign	not specified	2016-07-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000273165	SCV000477315	likely benign	Telangiectasia, hereditary hemorrhagic, type 1	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000858405	SCV000557849	benign	Hereditary hemorrhagic telangiectasia	2024-01-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000273165	SCV000603466	benign	Telangiectasia, hereditary hemorrhagic, type 1	2023-10-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001610455	SCV001839978	benign	not provided	2018-12-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25312062, 15024723, 22022569, 20981092, 19767588, 25637381, 22995991, 24055113)
Ambry Genetics	RCV002390308	SCV002703627	benign	Cardiovascular phenotype	2016-06-16	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV001610455	SCV004010860	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ENG: BP4, BS2
CSER _CC_NCGL, University of Washington	RCV000148485	SCV000190188	uncertain significance	Haemorrhagic telangiectasia 1	2014-06-01	no assertion criteria provided	research