Submissions for variant NM_001114753.3(ENG):c.1319T>G (p.Val440Gly)

dbSNP: rs1554809363

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV001285345	SCV005438641	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2024-11-12	reviewed by expert panel	curation	The NM_001114753.3: c.1319T>G variant in ENG is a missense variant predicted to cause substitution of valine by glycine at amino acid 440 (p.Val440Gly). This variant has been reported in more than 2 probands with a phenotype consistent with HHT (PS4_Moderate; 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; Internal lab contributors). The variant has been reported to segregate with Hereditary Hemorrhagic Telangiectasia in 5 affected meioses from 1 family (PP1_Strong; Internal lab contributors). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.385, 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: PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting (specifications version 1.1.0; 11/12/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633145	SCV000754359	pathogenic	Hereditary hemorrhagic telangiectasia	2023-08-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 528065). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val440 amino acid residue in ENG. Other variant(s) that disrupt this residue have been observed in individuals with ENG-related conditions (PMID: 34872578; Invitae), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ENG protein function. This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 440 of the ENG protein (p.Val440Gly).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001285345	SCV001471759	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 1	2020-03-12	criteria provided, single submitter	clinical testing	The ENG c.1319T>G; p.Val440Gly variant, to our knowledge, is not reported in the medical literature but is reported in the ClinVar database (Variation ID: 528065). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 440 is a moderately conserved residue in the zona pellucida domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, a different variant at this codon (p.Val440Met) is reported in the HHT variant database (see link). However, due to limited information, the clinical significance of the p.Val440Gly variant is uncertain at this time. REFERENCES ENG HHT database link: https://arup.utah.edu/database/ENG/ENG_display.php
Ambry Genetics	RCV002385994	SCV002691804	likely pathogenic	Cardiovascular phenotype	2023-05-22	criteria provided, single submitter	clinical testing	The p.V440G variant (also known as c.1319T>G), located in coding exon 11 of the ENG gene, results from a T to G substitution at nucleotide position 1319. The valine at codon 440 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with hereditary hemorrhagic telangiectasia (HHT) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480725	SCV004225102	uncertain significance	not provided	2022-12-07	criteria provided, single submitter	clinical testing	PM2_supporting
GeneDx	RCV003480725	SCV005370260	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function