Submissions for variant NM_001127222.2(CACNA1A):c.5650G>A (p.Val1884Ile)

gnomAD frequency: 0.00070  dbSNP: rs201836062

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726584	SCV000524685	benign	not provided	2021-05-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726584	SCV000701646	uncertain significance	not provided	2017-07-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088540	SCV000775252	likely benign	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2024-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002318439	SCV000849689	likely benign	Inborn genetic diseases	2017-06-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Athena Diagnostics	RCV001706630	SCV001880208	benign	not specified	2021-04-05	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224276	SCV003920648	likely benign	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42	2022-08-18	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.2% (85/41384) (https://gnomad.broadinstitute.org/variant/19-13224748-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:384036). This variant amino acid Isoleucine (Ile) is present in several species; this suggests that this variant may not impact the protein. However, additional computational prediction tools do suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003985336	SCV004722467	likely benign	CACNA1A-related disorder	2022-02-08	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001706630	SCV005077444	likely benign	not specified	2024-04-04	criteria provided, single submitter	clinical testing	Variant summary: CACNA1A c.5653G>A (p.Val1885Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 238884 control chromosomes, suggesting that the variant may be benign. To our knowledge, no occurrence of c.5653G>A in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 384036). Based on the evidence outlined above, the variant was classified as likely benign.