Submissions for variant NM_000069.3(CACNA1S):c.1945A>C (p.Asn649His)

gnomAD frequency: 0.00013  dbSNP: rs760246258

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000267151	SCV000353075	likely benign	Hypokalemic periodic paralysis, type 1	2018-01-12	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000651225	SCV000773076	uncertain significance	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 649 of the CACNA1S protein (p.Asn649His). This variant is present in population databases (rs760246258, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1S-related conditions. ClinVar contains an entry for this variant (Variation ID: 294752). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1S protein function with a positive predictive value of 80%. 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.
GeneDx	RCV000994231	SCV001778888	uncertain significance	not provided	2023-10-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV003298356	SCV003990671	uncertain significance	Inborn genetic diseases	2023-05-23	criteria provided, single submitter	clinical testing	The c.1945A>C (p.N649H) alteration is located in exon 13 (coding exon 13) of the CACNA1S gene. This alteration results from a A to C substitution at nucleotide position 1945, causing the asparagine (N) at amino acid position 649 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV000651225	SCV001749819	not provided	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-18-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.