ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.2992G>A (p.Asp998Asn) (rs116347156)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000210902 SCV000264596 uncertain significance Malignant hyperthermia susceptibility 2015-12-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000320288 SCV000353016 benign Hypokalemic periodic paralysis 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx RCV000493592 SCV000582249 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1S gene. The D998N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D998N variant is observed in 62/10340 (0.6%) alleles from individuals of African background in the ExAC dataset, which is greater than expected for this disorder (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D998N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with CACNA1S-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001079169 SCV000653685 benign Hypokalemic periodic paralysis 1; Malignant hyperthermia, susceptibility to, 5 2019-12-31 criteria provided, single submitter clinical testing

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