Submissions for variant NM_001114753.3(ENG):c.1844C>T (p.Ser615Leu)

gnomAD frequency: 0.00134  dbSNP: rs148002300

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV000230696	SCV004805880	likely benign	Telangiectasia, hereditary hemorrhagic, type 1	2024-03-15	reviewed by expert panel	curation	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).
Invitae	RCV001079415	SCV000283534	likely benign	Hereditary hemorrhagic telangiectasia	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000243657	SCV000302339	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000230696	SCV000477309	likely benign	Telangiectasia, hereditary hemorrhagic, type 1	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000756073	SCV000512936	likely benign	not provided	2020-02-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15712270, 24055113, 25637381, 22022569, 25312062, 30487145)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000243657	SCV000539097	likely benign	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.4% (108/26946) European chromosomes
SIB Swiss Institute of Bioinformatics	RCV000230696	SCV000803471	likely benign	Telangiectasia, hereditary hemorrhagic, type 1	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Benign, for Telangiectasia, hereditary hemorrhagic, type 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder (http://exac.broadinstitute.org/variant/9-130578230-G-A). BS2-Supporting => BS2 downgraded in strength to supporting. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:15712270).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000230696	SCV000883788	benign	Telangiectasia, hereditary hemorrhagic, type 1	2023-06-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000230696	SCV001137908	benign	Telangiectasia, hereditary hemorrhagic, type 1	2019-05-28	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000230696	SCV001439440	benign	Telangiectasia, hereditary hemorrhagic, type 1	2018-01-01	criteria provided, single submitter	research	BS1 +BP2+BP6
Ambry Genetics	RCV002408654	SCV002712662	likely benign	Cardiovascular phenotype	2017-03-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000756073	SCV004810481	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	ENG: BP4, BS1, BS2
CSER _CC_NCGL, University of Washington	RCV000148482	SCV000190184	likely benign	Haemorrhagic telangiectasia 1	2014-06-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000756073	SCV001807556	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000756073	SCV001921146	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000756073	SCV001929365	likely benign	not provided		no assertion criteria provided	clinical testing