ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.262A>G (p.Lys88Glu) (rs140330831)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000729718 SCV000572593 uncertain significance not provided 2018-09-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1S gene. The K88E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The K88E variant is is observed in 34/66716 (0.05%) alleles from individuals of non-Finnish European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K88E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000651220 SCV000773071 uncertain significance Hypokalemic periodic paralysis 1; Malignant hyperthermia susceptibility type 5 2017-10-12 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 88 of the CACNA1S protein (p.Lys88Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs140330831, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CACNA1S-related disease. ClinVar contains an entry for this variant (Variation ID: 422981). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000729718 SCV000857404 uncertain significance not provided 2017-10-06 criteria provided, single submitter clinical testing

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