ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.4991G>A (p.Arg1664Gln) (rs121908247)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000716048 SCV000846881 likely pathogenic History of neurodevelopmental disorder 2018-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Athena Diagnostics Inc RCV000406556 SCV000612550 likely pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing
Baylor Genetics RCV000679889 SCV000807290 uncertain significance Episodic ataxia type 2 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found four times in our laboratory as de novo findings in affected individuals.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415457 SCV000492918 likely pathogenic Global developmental delay; Enlarged cisterna magna 2014-05-20 criteria provided, single submitter clinical testing
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital,College of Medicine, The Catholic University of Korea RCV000755049 SCV000882749 pathogenic Ataxia _ Neurologic (child onset); Non-progressive congenital cerebellar ataxia 2019-02-11 no assertion criteria provided research
GeneDx RCV000406556 SCV000329829 pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing The R1664Q variant in the CACNA1A gene has been reported previously as a de novo variant in a child with early-onset non-fluctuating limb and truncal ataxia (Tonelli et al., 2006). The R1664Q variant has also been reported as de novo in four unrelated individuals with global developmental delay, hypotonia, early-onset ataxia, and ophthalmologic abnormalities (Luo et al., 2017). Functional studies show that the variant significantly impairs the function of the protein (Luo et al., 2017). The R1664Q variant is not observed in large population cohorts (Lek et al., 2016). The R1664Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Missense variants in nearby residues (R1661H, R1667W) have been reported in the Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R1664Q as a pathogenic variant
Invitae RCV000653331 SCV000775210 pathogenic Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2018-01-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1664 of the CACNA1A protein (p.Arg1664Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in several individuals affected with early onset ataxia (PMID: 16325861, 28742085). ClinVar contains an entry for this variant (Variation ID: 68432). Experimental studies have shown that this missense change results in reduced protein activity and can only partially rescue the synaptic transmission defect caused by null mutations in Drosophila (PMID: 28742085). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000157057 SCV000199322 pathogenic Chronic and progressive ataxia 2014-11-30 no assertion criteria provided clinical testing
UniProtKB/Swiss-Prot RCV000059302 SCV000090860 not provided Spinocerebellar ataxia 6 no assertion provided not provided

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