Submissions for variant NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His)

dbSNP: rs28930068

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000414086	SCV000342944	pathogenic	not provided	2016-06-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000414086	SCV000490450	pathogenic	not provided	2022-01-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate membrane depolarization (Jurkat-Rott et al., 2009); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10639629, 7847370, 16767662, 30090141, 11555352, 17418573, 19225109, 28857175, 31068157, 31567646, 33184660, 29572832, 11591859, 33042247, 9066893, 7650604, 19118277)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627793	SCV000653633	pathogenic	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1239 of the CACNA1S protein (p.Arg1239His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hypokalemic periodic paralysis (PMID: 7847370, 10639629, 11555352, 17418573, 21841462, 25213595). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17623). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1S protein function. Experimental studies have shown that this missense change affects CACNA1S function (PMID: 19225109). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000019190	SCV000803550	pathogenic	Hypokalemic periodic paralysis, type 1	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Pathogenic, for Periodic paralysis hypokalemic 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:8004673). PS2 => De novo (paternity and maternity confirmed). Only paternity confirmed, but since article has been published in 1994, we can assume no need to confirm maternity (PMID:8004673). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation (PMID:8004673,18162704,17418573,19118277). PS3 => Well-established functional studies show a deleterious effect (PMID:28857175,29572832).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000019190	SCV001976700	pathogenic	Hypokalemic periodic paralysis, type 1	2021-10-01	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP3, PP5
3billion, Medical Genetics	RCV000019190	SCV002012153	pathogenic	Hypokalemic periodic paralysis, type 1	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novo and observed in at least two similarly affected unrelated individuals (PMID:34008892, 26252573, PS2, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:29572832, 28857175, 19225109, PS3). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg1239Gly) has been reported as pathogenic (VCV000017624.7, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.971, 3Cnet: 0.869, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DASA	RCV000019190	SCV002061170	pathogenic	Hypokalemic periodic paralysis, type 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.3716G>A;p.(Arg1239His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17623; OMIM: 114208.0001; PMID: 34008892; 11555352; 21841462; 25213595; 20301512PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 19225109; 29572832) - PS3_moderate. This variant is not present in population databases (rs28930068, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 17624 - c.3715C>G;p.(Arg1239Gly) - ) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 34008892) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 7847370; 17418573; 11555352) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000414086	SCV002562964	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450645	SCV004177653	pathogenic	Malignant hyperthermia, susceptibility to, 5	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000019190	SCV004177654	pathogenic	Hypokalemic periodic paralysis, type 1	2023-04-11	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000414086	SCV004229525	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with HOKPP and segregates with disease in multiple families. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools predict that this variant is damaging.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003992159	SCV004810028	uncertain significance	Congenital myopathy 18	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000019190	SCV000039478	pathogenic	Hypokalemic periodic paralysis, type 1	1995-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000019190	SCV000040412	not provided	Hypokalemic periodic paralysis, type 1		no assertion provided	literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV000019190	SCV002600038	pathogenic	Hypokalemic periodic paralysis, type 1	2022-04-12	no assertion criteria provided	research