rs1555515597
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_004360.5(CDH1):c.833G>A(p.Gly278Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G278A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.833G>A | p.Gly278Glu | missense_variant, splice_region_variant | 7/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.833G>A | p.Gly278Glu | missense_variant, splice_region_variant | 7/15 | ||
CDH1 | NM_001317185.2 | c.-783G>A | splice_region_variant, 5_prime_UTR_variant | 7/16 | |||
CDH1 | NM_001317186.2 | c.-987G>A | splice_region_variant, 5_prime_UTR_variant | 7/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.833G>A | p.Gly278Glu | missense_variant, splice_region_variant | 7/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 16, 2020 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CDH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 278 of the CDH1 protein (p.Gly278Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 06, 2019 | The p.G278E variant (also known as c.833G>A) is located in coding exon 7 of the CDH1 gene. The glycine at codon 278 is replaced by glutamic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 7. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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