ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.1145G>A (p.Cys382Tyr)

dbSNP: rs1131691931
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494433 SCV000583167 likely pathogenic not provided 2015-08-26 criteria provided, single submitter clinical testing The C382Y variant has not been published as a pathogenic variant nor has it been reported as a benign polymorphism to our knowledge. The C382Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C382Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Furthermore, missense variants in the same residue (C382G, C382W) have been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014), supporting the functional importance of this residue. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function
Ambry Genetics RCV002455955 SCV002613625 uncertain significance Cardiovascular phenotype 2016-10-06 criteria provided, single submitter clinical testing The p.C382Y variant (also known as c.1145G>A), located in coding exon 9 of the ENG gene, results from a G to A substitution at nucleotide position 1145. The cysteine at codon 382 is replaced by tyrosine, an amino acid with highly dissimilar properties. Other variants affecting the same residue (p.C382W and p.C382G) have been reported in patients with hereditary hemorrhagic telangiectasia (Bayrak-Toydemir P et al. Genet. Med., 2004 Aug;6:175-91; Olivieri C et al. J. Hum. Genet., 2007 Sep;52:820-9). The p.C382Y variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV002524049 SCV003483993 pathogenic Hereditary hemorrhagic telangiectasia 2023-05-20 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 382 of the ENG protein (p.Cys382Tyr). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 30763665; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters ENG gene expression (PMID: 30763665). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ENG protein function. ClinVar contains an entry for this variant (Variation ID: 430375).

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