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

gnomAD frequency: 0.00016  dbSNP: rs140330831

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000729718	SCV000572593	uncertain significance	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Reported previously in an individual who underwent exome sequencing, however clinical information was not provided and segregation analysis was not performed (Gonsalves et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24195946)
Invitae	RCV000651220	SCV000773071	benign	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2024-01-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000729718	SCV000857404	uncertain significance	not provided	2017-10-06	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001356678	SCV002577488	uncertain significance	Hypokalemic periodic paralysis, type 1	2022-06-28	criteria provided, single submitter	clinical testing	PM2, PP3
Fulgent Genetics, Fulgent Genetics	RCV002481529	SCV002785460	uncertain significance	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5; Thyrotoxic periodic paralysis, susceptibility to, 1	2022-02-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002526644	SCV003639301	uncertain significance	Inborn genetic diseases	2021-09-09	criteria provided, single submitter	clinical testing	The c.262A>G (p.K88E) alteration is located in exon 3 (coding exon 3) of the CACNA1S gene. This alteration results from a A to G substitution at nucleotide position 262, causing the lysine (K) at amino acid position 88 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001356834	SCV004360416	uncertain significance	Malignant hyperthermia, susceptibility to, 5	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 88 of the CACNA1S protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CACNA1S-related disorders in the literature. This variant has been identified in 67/282844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356134	SCV001551208	uncertain significance	Thyrotoxic periodic paralysis, susceptibility to, 1		no assertion criteria provided	clinical testing	The CACNA1S p.Lys88Glu variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Variant of uncertain significance; classified as uncertain significance by Invitae in 2017, EGL Genetic Diagnostics in 2017, and GeneDx in 2018), LOVD 3.0 (1 submission, likely benign) and dbSNP (rs140330831, Uncertain) databases. The variant was identified in control databases in 67 of 282844 chromosomes at a frequency of 0.0002369 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 57 of 129164 chromosomes (freq: 0.000441), Other in 2 of 7224 chromosomes (freq: 0.000277), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193), European (Finnish) in 3 of 25120 chromosomes (freq: 0.000119), Latino in 3 of 35440 chromosomes (freq: 0.000085), but was not observed in the African, East Asian, or South Asian populations. The variant was identified in 1/1740 alleles of adults unselected for malignant hyperthermia (Gonsalves_2013_PMID: 24195946). The p.Lys88 residue is conserved in mammals but not in more istantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.Disease Information: Heterozygous pathogenic variants in CACNA1S cause hypokalemic periodic paralysis type 1 (OMIM: 170400).  Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. (Verbatim, GeneReviews) Heterozygous pathogenic variants in CACNA1S are also associated with susceptibility to malignant hyperthermia (OMIM: 601887). Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for renal failure. (Verbatim, GeneReviews) Heterozygous pathogenic variants in CACNA1S are also associated with susceptibility to thyrotoxic periodic paralysis (OMIM: 188580). Thyrotoxic periodic paralysis is a sporadic muscle disorder characterized by episodic attacks of weakness associated with hypokalemia in individuals with hyperthyroidism. The paralysis resolves upon treatment of hyperthyroidism (OMIM: 188580)Familial Risk: Hypokalemic periodic paralysis, susceptibility to malignant hyperthermia, and susceptibility to thyrotoxic periodic paralysis are all inherited in an autosomal dominant manner. Each offspring of an individual with a variant has a 50% chance of inheriting the variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356678	SCV001551914	uncertain significance	Hypokalemic periodic paralysis, type 1		no assertion criteria provided	clinical testing	The CACNA1S p.Lys88Glu variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Variant of uncertain significance; classified as uncertain significance by Invitae in 2017, EGL Genetic Diagnostics in 2017, and GeneDx in 2018), LOVD 3.0 (1 submission, likely benign) and dbSNP (rs140330831, Uncertain) databases. The variant was identified in control databases in 67 of 282844 chromosomes at a frequency of 0.0002369 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 57 of 129164 chromosomes (freq: 0.000441), Other in 2 of 7224 chromosomes (freq: 0.000277), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193), European (Finnish) in 3 of 25120 chromosomes (freq: 0.000119), Latino in 3 of 35440 chromosomes (freq: 0.000085), but was not observed in the African, East Asian, or South Asian populations. The variant was identified in 1/1740 alleles of adults unselected for malignant hyperthermia (Gonsalves_2013_PMID: 24195946). The p.Lys88 residue is conserved in mammals but not in more istantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.Disease Information: Heterozygous pathogenic variants in CACNA1S cause hypokalemic periodic paralysis type 1 (OMIM: 170400).  Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. (Verbatim, GeneReviews) Heterozygous pathogenic variants in CACNA1S are also associated with susceptibility to malignant hyperthermia (OMIM: 601887). Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for renal failure. (Verbatim, GeneReviews) Heterozygous pathogenic variants in CACNA1S are also associated with susceptibility to thyrotoxic periodic paralysis (OMIM: 188580). Thyrotoxic periodic paralysis is a sporadic muscle disorder characterized by episodic attacks of weakness associated with hypokalemia in individuals with hyperthyroidism. The paralysis resolves upon treatment of hyperthyroidism (OMIM: 188580)Familial Risk: Hypokalemic periodic paralysis, susceptibility to malignant hyperthermia, and susceptibility to thyrotoxic periodic paralysis are all inherited in an autosomal dominant manner. Each offspring of an individual with a variant has a 50% chance of inheriting the variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356834	SCV001552105	uncertain significance	Malignant hyperthermia, susceptibility to, 5		no assertion criteria provided	clinical testing	The CACNA1S p.Lys88Glu variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Variant of uncertain significance; classified as uncertain significance by Invitae in 2017, EGL Genetic Diagnostics in 2017, and GeneDx in 2018), LOVD 3.0 (1 submission, likely benign) and dbSNP (rs140330831, Uncertain) databases. The variant was identified in control databases in 67 of 282844 chromosomes at a frequency of 0.0002369 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 57 of 129164 chromosomes (freq: 0.000441), Other in 2 of 7224 chromosomes (freq: 0.000277), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193), European (Finnish) in 3 of 25120 chromosomes (freq: 0.000119), Latino in 3 of 35440 chromosomes (freq: 0.000085), but was not observed in the African, East Asian, or South Asian populations. The variant was identified in 1/1740 alleles of adults unselected for malignant hyperthermia (Gonsalves_2013_PMID: 24195946). The p.Lys88 residue is conserved in mammals but not in more istantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.