ClinVar Miner

Submissions for variant NM_001242897.2(DEPDC5):c.842A>T (p.Tyr281Phe) (rs200797928)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486977 SCV000569491 uncertain significance not provided 2018-10-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DEPDC5 gene. The Y281F variant has been reported previously in a child with infantile spasms, speech delay, hemiparesis, and focal cortical dysplasia, in addition to the child's father with unclassified epilepsy and sister with multifocal epilepsy; however, functional studies were not performed (Carvill et al., 2015). The Y281F variant is observed in 3/24008 (0.01%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The Y281F 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000718618 SCV000849482 uncertain significance Seizures 2017-04-17 criteria provided, single submitter clinical testing The p.Y281F variant (also known as c.842A>T), located in coding exon 12 of the DEPDC5 gene, results from an A to T substitution at nucleotide position 842. The tyrosine at codon 281 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been reported in an individual with infantile spasms and focal cortical dysplasia on MRI; in addition, this variant was inherited from a father with unspecified epilepsy and also detected in a full sibling with multifocal epilepsy (Carvill GL et al. Neurol Genet, 2015 Aug;1:e17). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001045891 SCV001209765 uncertain significance Familial focal epilepsy with variable foci 2019-09-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with phenylalanine at codon 281 of the DEPDC5 protein (p.Tyr281Phe). The tyrosine residue is highly conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is present in population databases (rs200797928, ExAC 0.008%). This variant has been observed to segregate with epilepsy in a family (PMID: 27066554). ClinVar contains an entry for this variant (Variation ID: 264753). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C15"). 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.
GeneReviews RCV000254604 SCV000321049 uncertain significance Epilepsy, familial focal, with variable foci 1 2016-04-13 no assertion criteria provided literature only

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