ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1446A>T (p.Glu482Asp)

gnomAD frequency: 0.00001  dbSNP: rs863224724
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000196042 SCV000254812 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-07-10 criteria provided, single submitter clinical testing 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 482 of the CDH1 protein (p.Glu482Asp). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 216587).
GeneDx RCV000216175 SCV000279976 uncertain significance not provided 2017-03-28 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.1446A>T at the cDNA level, p.Glu482Asp (E482D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Glu482Asp was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. CDH1 Glu482Asp occurs at a position that is conserved across species and is located in the Cadherin 3 domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CDH1 Glu482Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001011623 SCV001171966 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-17 criteria provided, single submitter clinical testing The p.E482D variant (also known as c.1446A>T), located in coding exon 10 of the CDH1 gene, results from an A to T substitution at nucleotide position 1446. The glutamic acid at codon 482 is replaced by aspartic acid, an amino acid with highly similar properties. 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 alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV001011623 SCV001354410 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-04 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with aspartic acid at codon 482 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 1/31388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc. RCV000196042 SCV005406818 likely benign Hereditary diffuse gastric adenocarcinoma 2024-09-19 criteria provided, single submitter clinical testing This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.

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