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

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547249	SCV000656723	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2019-07-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). This variant has not been reported in the literature in individuals with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 476239). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln681Argfs*17) in the CACNA1A gene. It is expected to result in an absent or disrupted protein product.
CeGaT Center for Human Genetics Tuebingen	RCV001531294	SCV001746324	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317277	SCV004020794	pathogenic	Developmental and epileptic encephalopathy, 42	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: CACNA1A c.2042delA (p.Gln681ArgfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 249244 control chromosomes (gnomAD). c.2042delA has been reported in the literature in 2 sisters affected with episodic ataxia and intellectual deficiency (Humbertclaude_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29926469). Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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