Submissions for variant NM_001114753.3(ENG):c.1268A>G (p.Asn423Ser)

dbSNP: rs1830431553

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV001262090	SCV005438642	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2024-11-12	reviewed by expert panel	curation	The NM_001114753.3: c.1268A>G variant in ENG is a missense variant predicted to cause substitution of asparagine by serine at amino acid 423 (p.Asn423Ser). This variant has been reported in more than 4 probands with a phenotype consistent with HHT (PS4; PMID: 32573726, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; PMID: 34872578). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.490, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as likely pathogenic 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: PS4, PP4_Moderate, PM2_Supporting (specifications version 1.1.0; 11/12/2024).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001262090	SCV001439482	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2018-01-01	criteria provided, single submitter	research	PM2+PP3+PP4
GeneDx	RCV001785803	SCV002027857	uncertain significance	not provided	2021-05-20	criteria provided, single submitter	clinical testing	Observed in an individual with pulmonary arterial hypertension (Song et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate subcellular localization of the endoglin protein similar to wild type (Ali et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22022569, 27613157)
Genetic Services Laboratory, University of Chicago	RCV001819966	SCV002069128	uncertain significance	not specified	2018-04-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003405470	SCV004112060	uncertain significance	ENG-related disorder	2023-04-27	criteria provided, single submitter	clinical testing	The ENG c.1268A>G variant is predicted to result in the amino acid substitution p.Asn423Ser. This variant was reported in an individual with pulmonary arterial hypertension (Song et al. 2016. PubMed ID: 27613157) and in an individual with hereditary hemorrhagic telangiectasia (HHT) (Kitayama et al. 2021. PubMed ID: 34872578). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has conflicting interpretations in ClinVar ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/982495/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004035394	SCV005037490	likely pathogenic	Cardiovascular phenotype	2024-09-02	criteria provided, single submitter	clinical testing	The p.N423S variant (also known as c.1268A>G), located in coding exon 9 of the ENG gene, results from an A to G substitution at nucleotide position 1268. The asparagine at codon 423 is replaced by serine, an amino acid with highly similar properties. This variant has been detected in multiple individuals meeting clinical criteria for hereditary hemorrhagic telangiectasia (HHT) or with features consistent with HHT, and segregated with disease in at least one family (Song J et al. Clin Sci (Lond), 2016 Nov;130:2043-2052; Shovlin CL et al. Blood, 2020 Oct;136:1907-1918; Kitayama K et al. BMC Med Genomics, 2021 Dec;14:288; external communication; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.