Submissions for variant NM_001242896.3(DEPDC5):c.562+1G>A

dbSNP: rs1057524233

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433181	SCV000534956	pathogenic	not provided	2019-06-20	criteria provided, single submitter	clinical testing	Reported in an individual with borderline intellectual disability and focal epilepsy. Inherited from mother who was also diagnosed with epilepsy. Although c.562+1G>A was considered pathogenic by the authors, affected individual also carried variants in two additional genes associated with seizures (Snoeijen-Schouwenaars et al., 2019).; Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30525188)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001038460	SCV001201929	pathogenic	Familial focal epilepsy with variable foci	2019-07-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the DEPDC5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with epilepsy and/or intellectual disability (PMID: 30525188) and has been reported to segregate with nocturnal epilepsy in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 391802). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DEPDC5 are known to be pathogenic (PMID: 23542697, 23542701). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594062	SCV005086681	pathogenic	Epilepsy, familial focal, with variable foci 1	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial focal epilepsy with variable foci 1 (MIM#604364). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Unaffected individuals with pathogenic familial variants are commonly reported, with penetrance estimated to be between 66% and 70% (PMIDs: 30767899, 32848577). (I) 0115 - Variants in this gene are known to have variable expressivity. Disease presentation in affected individuals is known to vary considerably even within the same family, from mild febrile seizures to severe focal epilepsy with cortical malformations (PMIDs: 27066554, 32848577). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0710 - Another splice variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This variant has been reported in an individual compound heterozygous with a missense variant, c.2507A>G, who has focal epilepsy (PMID: 34489640). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in three individuals as likely pathogenic / pathogenic, one of which was maternally inherited from an affected mother diagnosed with epilepsy (ClinVar, PMID: 30525188). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign