ClinVar Miner

Submissions for variant NM_172364.5(CACNA2D4):c.2406C>A (p.Tyr802Ter)

gnomAD frequency: 0.00057  dbSNP: rs71454844
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000002610 SCV000377243 uncertain significance Retinal cone dystrophy 4 2017-04-28 criteria provided, single submitter clinical testing The CACNA2D4 c.2406C>A (p.Tyr802Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Tyr802Ter variant has been reported in one study in which it is found in a homozygous state in two siblings with retinal cone dystrophy (Wycisk et al. 2006). The variant allele was absent in the unaffected siblings and present in a heterozygous state in the unaffected father. The p.Tyr802Ter variant was absent from 224 controls and is reported at a frequency of 0.00067 in the European (non-Finnish) population of the Exome Aggregation Consortium. Bacchi et al. (2015) reported that the variant results in the abolition of a predicted exon splicing enhancer and the creation of an exon splicing silencer. Due to the potential impact of stop-gained variants and the supporting evidence from the literature, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for retinal cone dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000519504 SCV000617848 likely pathogenic not provided 2021-03-10 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17033974, 26218913, 31980526, 32967234, 32607809)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825880 SCV000967365 uncertain significance not specified 2018-11-20 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic.
Invitae RCV000519504 SCV001230064 uncertain significance not provided 2024-01-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr802*) 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 (rs71454844, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with CACNA2D4-related conditions (PMID: 17033974, 36460718). ClinVar contains an entry for this variant (Variation ID: 2504). 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.
Revvity Omics, Revvity RCV000002610 SCV002025046 likely pathogenic Retinal cone dystrophy 4 2019-07-22 criteria provided, single submitter clinical testing
OMIM RCV000002610 SCV000022768 pathogenic Retinal cone dystrophy 4 2006-11-01 no assertion criteria provided literature only

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