ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.2039_2040del (p.Gln680fs)

dbSNP: rs1064794262
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482772 SCV000568531 pathogenic not provided 2022-03-09 criteria provided, single submitter clinical testing Frameshift 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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27479843, 20396531, 27667184, 20129625, 28566750, 11960817, 32581362, 10371528, 12420090)
Athena Diagnostics RCV000482772 SCV000612513 pathogenic not provided 2023-06-23 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with episodic ataxia in multiple families and has been confirmed to occur de novo in one individual.
Labcorp Genetics (formerly Invitae), Labcorp RCV001059907 SCV001224561 pathogenic Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2023-08-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 420056). This variant is also known as "deletion AG 2259-60" and c.2145_2148delAG. This premature translational stop signal has been observed in individual(s) with episodic ataxia type 2 (PMID: 10371528, 12420090, 20129625, 20396531, 28566750). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln681Argfs*100) in the CACNA1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579).
CeGaT Center for Human Genetics Tuebingen RCV000482772 SCV001501690 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000482772 SCV002018025 pathogenic not provided 2019-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001799666 SCV002044453 likely pathogenic Developmental and epileptic encephalopathy, 42 2022-03-30 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PVS1, PS4_MOD, PS2_SUP
MGZ Medical Genetics Center RCV001799666 SCV002581217 pathogenic Developmental and epileptic encephalopathy, 42 2022-02-10 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV003114604 SCV003799132 pathogenic Episodic ataxia type 2 2022-10-25 criteria provided, single submitter clinical testing PVS1, PS4_Moderate, PM2
PreventionGenetics, part of Exact Sciences RCV003985358 SCV004118740 pathogenic CACNA1A-related disorder 2023-08-17 criteria provided, single submitter clinical testing The CACNA1A c.2039_2040delAG variant is predicted to result in a frameshift and premature protein termination (p.Gln680Argfs*100). This variant is alternatively referred to as c.2042_2043delAG (p.Gln681Argfs*100). This variant has been reported de novo in an individual from an intellectual disability cohort (Table S2, Lelieveld et al. 2016. PubMed ID: 27479843). It has also been reported in three individuals with episodic ataxia; in one of these individuals the variant was confirmed to have arisen de novo (referred to as c.2137_2318delAG, Family 2, Figure 1, van den Maagdenberg et al. 2002. PubMed ID: 12420090; Table 1, Sintas et al. 2017. PubMed ID: 28566750; Table 1, Zhang et al. 2020. PubMed ID: 33425808). One individual with episodic ataxia that harbored this variant also exhibited nystagmus, and language developmental delay, but was not reported to have seizures (Table 1, Zhang et al. 2020. PubMed ID: 33425808). It has also been reported in an individual undergoing exome sequencing (Table S2, Turro et al. 2020. PubMed ID: 32581362). This variant is reported in 1 of ~249,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/19-13414644-CCT-C). Frameshift variants in CACNA1A are expected to be pathogenic. This variant is interpreted as pathogenic.
Ambry Genetics RCV004023135 SCV004916230 pathogenic Inborn genetic diseases 2024-02-13 criteria provided, single submitter clinical testing The c.2042_2043delAG (p.Q681Rfs*100) alteration, located in exon 16 (coding exon 16) of the CACNA1A gene, consists of a deletion of 2 nucleotides from position 2042 to 2043, causing a translational frameshift with a predicted alternate stop codon after 100 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay._x000D_ _x000D_ for episodic ataxia, type 2; however, its clinical significance for CACNA1A-related neurologic disorder is uncertain, and it is unlikely to be causative of CACNA1A-related spinocerebellar ataxia. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/249250) total alleles studied. The highest observed frequency was 0.001% (1/113012) of European (non-Finnish) alleles. This variant was reported in multiple individuals with recurrent episodes of ataxia and has been shown to segregate with disease in one family with varying severities of episodic ataxia type 2 (Denier, 1999; Kim, 2006; Mantuano, 2010; Sintas, 2017). Additionally, this variant has been determined to be the result of a de novo mutation in two individuals with episodic ataxia and nystagmus (van den Maagdenberg, 2002; Zhang, 2020). Based on the available evidence, this alteration is classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001004002 SCV001162046 likely pathogenic Bulbar palsy; Recurrent respiratory infections; Epileptic encephalopathy no assertion criteria provided research

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