chr1-201077915-C-T

Variant names:

• chr1-201077915-C-T
• rs80338777
• NM_000069.3:c.1583G>A
• CACNA1S p.Arg528His

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 15 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPM5PP3_StrongPP5_Strong

The NM_000069.3(CACNA1S):c.1583G>A (p.Arg528His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000372 (AC=6) in the gnomAD database across 1,613,896 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.87). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001445907: Functional studies have demonstrated that this variant alters the electrophysiological properties of the calcium channel, including potassium-dependent paradoxical membrane depolarization (PMID:8605978, 9512357, 19225109), and a mouse model of this variant recapitulates the essential features of hypokalemic periodic paralysis in humans, including muscle weakness (PMID:23187123)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R528C: Pathogenic/Likely_pathogenic (ClinVar VariationId 849085, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R528S: Uncertain_significance (ClinVar VariationId 4689585, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Hypokalemic periodic paralysis, type 1 (hokpp1); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 U:1 O:1
• Conservation: PhyloP100: 7.87
• Publications: 90 publications found

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

CACNA1S Gene-Disease associations (from GenCC):

• hypokalemic periodic paralysis, type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• malignant hyperthermia, susceptibility to, 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR, SD, AD Classification: STRONG Submitted by: Genomics England PanelApp, Illumina
• congenital myopathy 18

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV001445907: Functional studies have demonstrated that this variant alters the electrophysiological properties of the calcium channel, including potassium-dependent paradoxical membrane depolarization (PMID: 8605978, 9512357, 19225109), and a mouse model of this variant recapitulates the essential features of hypokalemic periodic paralysis in humans, including muscle weakness (PMID: 23187123).; SCV007093832: The most pronounced variant effect results in enhance inactivation of the L-type calcium channel (Sipos_1995). PMID:7847370, PMID:7987325, PMID:7650604; SCV000491250: Published functional studies demonstrate that this variant results in a significantly reduced whole cell calcium channel current and depolarization of the resting cell potential in response to hypokalemia (Lapie et al., 1996; Wu et al., 2012); SCV000612594: This variant has been shown to disrupt CACNA1S calcium channel function, causing potassium-dependent paradoxical membrane depolarization in response to hypokalemia (PMID: 8605978, 19225109, 23187123).; SCV006325044: Mouse models of the p.Arg528His variant demonstrate a phenotype similar to autosomal dominant hypokalemic periodic paralysis type 1; functional studies of the mutant p.Arg528His calcium channel indicate reduced ionic current density and impaired voltage-dependent Ca2+ release compared to wild-type CACNA1S protein [PMID: 23187123].; SCV000653632: Experimental studies have shown that this missense change affects CACNA1S function (PMID: 8605978, 9512357, 9852570, 23187123).; SCV005352415: A mouse model of the p.Arg528His variant displays many of the human clinical features of hypokalemic periodic paralysis (Wu et al. 2012. PubMed ID: 23187123).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R528C: Pathogenic/Likely_pathogenic (ClinVar VariationId 849085, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R528S: Uncertain_significance (ClinVar VariationId 4689585, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (19/20 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000069.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CACNA1S NM_000069.3	MANE Select	c.1583G>A p.Arg528His	missense	Exon 11 of 44	Prot: NP_000060.2 UniProt:

CACNA1S NM_000069.3

MANE Select

HGVSc / HGVSpc.1583G>Ap.Arg528His

Exon rankExon 11 of 44

missense

Prot: NP_000060.2UniProt: Q13698

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CACNA1S ENST00000362061.4	TSL:1MANE Select	c.1583G>A p.Arg528His	missense	Exon 11 of 44	Prot: ENSP00000355192.3 UniProt:
	CACNA1S ENST00000367338.7	TSL:5	c.1583G>A p.Arg528His	missense	Exon 11 of 43	Prot: ENSP00000356307.3 UniProt:
	CACNA1S ENST00000681874.1		c.1583G>A p.Arg528His	missense	Exon 11 of 43	Prot: ENSP00000505162.1 UniProt:

CACNA1S ENST00000362061.4

TSL:1MANE Select

HGVSc / HGVSpc.1583G>Ap.Arg528His

Exon rankExon 11 of 44

missense

Prot: ENSP00000355192.3UniProt: Q13698

CACNA1S ENST00000367338.7

TSL:5

HGVSc / HGVSpc.1583G>Ap.Arg528His

Exon rankExon 11 of 43

missense

Prot: ENSP00000356307.3UniProt: B1ALM3

CACNA1S ENST00000681874.1

HGVSc / HGVSpc.1583G>Ap.Arg528His

Exon rankExon 11 of 43

missense

Prot: ENSP00000505162.1UniProt: A0A7P0T8M7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152214	Cov:33
GnomAD4 exome	AF: 0.00000342	AC:5	Hom:0	AN:1461682	Cov:30
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152214	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000485	AC:11	Hom:0	AN:226764	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122660	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000208 *	2	9622	0.00 *	0	10428
SCHEMA(Schizophrenia)	0.00	0	77642	0.00000718	1	139308

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Hypokalemic periodic paralysis, type 1 (10)
7	-	-	not provided (7)
1	-	-	CACNA1S-related disorder (1)
-	1	-	Malignant hyperthermia, susceptibility to, 5 (1)
1	-	-	Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1;C5830283:Congenital myopathy 18 (1)
1	-	-	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	27
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-8.1
GPN-Star score	N/A	8.1
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.99	D
Mutation Taster	N/A	10/90	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.3	H
PhyloP100	Pathogenic	7.9
popEVE	Benign	-3.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.93
VESM-3B	Benign	-13

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs80338777;

hg19: chr1-201047043;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar