ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.610G>A (p.Val204Ile)

dbSNP: rs876661028
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000221294 SCV000279263 uncertain significance not provided 2015-11-09 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.610G>A at the cDNA level, p.Val204Ile (V204I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Val204Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. CDH1 Val204Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the Cadherin 1 domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether CDH1 Val204Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000698915 SCV000827605 uncertain significance Hereditary diffuse gastric adenocarcinoma 2021-05-28 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 234454). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 204 of the CDH1 protein (p.Val204Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine.

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