Submissions for variant NM_001114753.3(ENG):c.1762G>A (p.Val588Ile)

gnomAD frequency: 0.00007  dbSNP: rs201768056

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV001169423	SCV005326485	likely benign	Telangiectasia, hereditary hemorrhagic, type 1	2024-09-11	reviewed by expert panel	curation	The NM_001114753.3: c.1762G>A variant in ENG is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 588 (p.Val588Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003436 (43/125140 alleles) in the non-Finnish European population. The computational predictor REVEL gives a score of 0.043, which is below the threshold of ≤0.1, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). This variant has been observed in a patient with an alternate molecular basis for disease (pathogenic variant identified in ACVRL1) (BP5; internal lab contributors). 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: BP4, BP5 (specifications version 1.1.0; 09/11/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233031	SCV000283532	likely benign	Hereditary hemorrhagic telangiectasia	2023-12-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000414391	SCV000491731	uncertain significance	not specified	2016-11-15	criteria provided, single submitter	clinical testing	The V588I variant of uncertain significance in the ENG gene has not been published as a pathogenicor benign variant to our knowledge. However, it is classified in ClinVar as a variant of uncertainsignificance in association with HHT by another clinical laboratory (ClinVar SCV000283532.1;Landrum et al., 2016). This variant was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. The V588I variant is a conservative amino acidsubstitution, which is not likely to impact secondary protein structure as these residues share similarproperties. This substitution also occurs at a position that is not conserved. Consequently, themajority of in silico tools predict V588I likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or rare benign.
Illumina Laboratory Services, Illumina	RCV001169423	SCV001332119	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Ambry Genetics	RCV002408948	SCV002716766	benign	Cardiovascular phenotype	2016-10-27	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	RCV003221872	SCV003917702	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	ENG: BP4