rs1060501415
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001114753.3(ENG):c.713T>A(p.Val238Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V238L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001114753.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENG | NM_001114753.3 | c.713T>A | p.Val238Glu | missense_variant | 6/15 | ENST00000373203.9 | |
ENG | NM_000118.4 | c.713T>A | p.Val238Glu | missense_variant | 6/14 | ||
ENG | NM_001278138.2 | c.167T>A | p.Val56Glu | missense_variant | 6/15 | ||
ENG | NM_001406715.1 | c.713T>A | p.Val238Glu | missense_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENG | ENST00000373203.9 | c.713T>A | p.Val238Glu | missense_variant | 6/15 | 1 | NM_001114753.3 | P2 | |
ENG | ENST00000344849.4 | c.713T>A | p.Val238Glu | missense_variant | 6/14 | 1 | A2 | ||
ENG | ENST00000480266.6 | c.167T>A | p.Val56Glu | missense_variant | 6/15 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 26
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 26
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 12, 2022 | PP1_strong, PM2_supporting, PS4_moderate - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2019 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 407121; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 20414677) - |
Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 02, 2023 | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 407121). This missense change has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 20414677; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 238 of the ENG protein (p.Val238Glu). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 05, 2018 | The p.V238E variant (also known as c.713T>A), located in coding exon 6 of the ENG gene, results from a T to A substitution at nucleotide position 713. The valine at codon 238 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration was described in individual with possible hereditary hemorrhagic telangiectasia based on pulmonary AVMs and a family history. Reportedly, the alteration segregated with disease in the family; however, the number of family members, clinical information on additional relatives, and the nature of the familial relationships were not described (Richards-Yutz J et al. Hum. Genet., 2010 Jul;128:61-77). This amino acid position is not well 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 alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at