Submissions for variant NM_172364.5(CACNA2D4):c.1276C>T (p.Arg426Ter)

gnomAD frequency: 0.00001  dbSNP: rs764495319

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778356	SCV000914571	uncertain significance	Retinal cone dystrophy 4	2018-10-11	criteria provided, single submitter	clinical testing	This variant is a stop-gained variant, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001346973	SCV001541211	uncertain significance	not provided	2024-07-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg426*) in the CACNA2D4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CACNA2D4 cause disease. This variant is present in population databases (rs764495319, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CACNA2D4-related conditions. ClinVar contains an entry for this variant (Variation ID: 631673). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GenomeConnect - Invitae Patient Insights Network	RCV001346973	SCV001749613	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.