Submissions for variant NM_001114753.3(ENG):c.1852+42C>T

gnomAD frequency: 0.00006  dbSNP: rs779974705

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001169422	SCV001332117	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001297217	SCV001486224	likely benign	Hereditary hemorrhagic telangiectasia	2023-07-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001169422	SCV004564533	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 1	2023-10-17	criteria provided, single submitter	clinical testing	The ENG c.1852+42C>T variant (rs779974705) is reported in the literature in an individual with HHT who presented with PAH as the main clinical manifestation (Plumitallo 2018). This variant was also found to segregate with HHT in two additional affected family members and was absent from two asymptomatic individuals (Plumitallo 2018). Functional analyses demonstrated this variant significantly reduces endoglin protein expression by altering a binding-site for the Sp1 transcription factor (Plumitallo 2018). This variant is reported in ClinVar (Variation ID: 914989). It is found in the general population with an overall allele frequency of 0.01% (24/217994 alleles) in the Genome Aggregation Database. Based on currently available information, the clinical significance of this variant is uncertain at this time. References: Plumitallo S et al. Functional analysis of a novel ENG variant in a patient with hereditary hemorrhagic telangiectasia (HHT) identifies a new Sp1 binding-site. Gene. 2018 Mar 20;647:85-92. PMID: 29305977.
PreventionGenetics, part of Exact Sciences	RCV003973123	SCV004792075	likely benign	ENG-related condition	2019-03-29	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).