Submissions for variant NM_001242897.2(DEPDC5):c.3030+3822C>T (rs772812141)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000456738	SCV000546507	uncertain significance	Familial focal epilepsy with variable foci	2019-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 1091 of the DEPDC5 protein (p.Ala1091Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs772812141, ExAC 0.08%). This variant has not been reported in the literature in individuals with DEPDC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 407344). 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"; Align-GVGD: "Class C0"). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786292	SCV000925053	uncertain significance	not provided	2017-04-08	no assertion criteria provided	provider interpretation	Found in a 14 year-old male with paroxysmal atrial fibrillation. He was tested at Invitae. p.Ala1091Val (c.3272C>T) in exon 33 of the DEPDC5 gene (NM_001242896.1; ENST00000400246.5) Chromosome position 22:32257361 C / T We classify this as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. Of note: The vast majority of Pathogenic variants in DEPDC5 currently listed in ClinVar are truncating (i.e. premature stop codon) and are not missense variants like this one. This variant has not previously been reported in the literature in association with disease. The DEPDC5 gene is associated with autosomal dominant familial focal epilepsy with variable foci (FFEVF) (MedGen UID: 348951). Our patient has no personal history of seizures, but his mother was diagnosed with epilepsy in her early 40s and his grandfather has a diagnosis of epilepsy as well. Mother and son both have a history of SVT, and our patient was diagnosed with paroxysmal atrial fibrillation at age 14. This is a conservative amino acid change, resulting in the replacement of a nonpolar alanine with a nonpolar valine. Alanine at this location is very highly conserved across the vertebrate species we have data for. No nearby missense variants (+/- 10 amino acids) have been listed as Likely Pathogenic or Pathogenic in ClinVar. Invitae reports that 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"; Align-GVGD: "Class C0"). In total the variant has been seen in at least 17 out of 90,960 individuals from publicly available population datasets. Specifically, this variant was reported in 15/11,411 individuals of South Asian ancestry, and in 2/36,377 with non-Finnish European ancestry, in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. This may be a low-quality site, given that there are no variant calls for 50,000 participants. There is one non-Finnish European individual with another missense change at this codon: p.Ala1091Asp. The highest allele frequency was 0.066% in South Asians. Overall allele frequency was 0.009%. Our patient’s ancestry is Northern European Caucasian. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.