Submissions for variant NM_001127222.2(CACNA1A):c.3411del (p.Lys1138fs)

dbSNP: rs746790849

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000500314	SCV000593813	pathogenic	Episodic ataxia type 2	2015-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001009007	SCV001168816	pathogenic	not provided	2018-08-30	criteria provided, single submitter	clinical testing	The c.3414delC variant in the CACNA1A gene has been reported previously in an individual with benign tonic upward gaze, episodic ataxia, and febrile seizures (Humbertclaude et al., 2018). The c.3414delC variant causes a frameshift starting with codon Lysine 1139, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 48 of the new reading frame, denoted p.Lys1139ArgfsX48. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3414delC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.3414delC as a pathogenic variant.
PreventionGenetics, part of Exact Sciences	RCV003985368	SCV004115060	pathogenic	CACNA1A-related disorder	2023-08-04	criteria provided, single submitter	clinical testing	The CACNA1A c.3411delC variant is predicted to result in a frameshift and premature protein termination (p.Lys1138Argfs*48). This variant has been reported in individuals with episodic ataxia (reported as c.3414delC in Humbertclaude et al. 2018. PubMed ID: 29926469; Sun et al. 2019. PubMed ID: 29915382). This variant is reported in 0.012% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13397458-TG-T). Frameshift variants in CACNA1A are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.