VCV000228247.12 - ClinVar

NM_001232.4(CASQ2):c.940-1G>T

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic

4 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001232.4(CASQ2):c.940-1G>T

Variation ID: 228247 Accession: VCV000228247.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p13.1 1: 115702996 (GRCh38) [ NCBI UCSC ] 1: 116245617 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 29, 2016	Feb 15, 2026	Apr 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001232.4:c.940-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NC_000001.11:g.115702996C>A
NC_000001.10:g.116245617C>A
NG_008802.1:g.70810G>T
LRG_404:g.70810G>T
LRG_404t1:c.940-1G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:115702995:C:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA10576356 dbSNP: rs876657635 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CASQ2		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	871	885

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Catecholaminergic polymorphic ventricular tachycardia	Likely pathogenic (1)	criteria provided, single submitter	Apr 13, 2015	RCV000222785.5
Catecholaminergic polymorphic ventricular tachycardia 1	Likely pathogenic (1)	criteria provided, single submitter	May 20, 2022	RCV002517522.5
Catecholaminergic polymorphic ventricular tachycardia 2	Likely pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV003343709.1
Catecholaminergic polymorphic ventricular tachycardia 1 Catecholaminergic polymorphic ventricular tachycardia 2	Likely pathogenic (1)	criteria provided, single submitter	Sep 14, 2021	RCV002503848.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Apr 13, 2015) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Catecholaminergic polymorphic ventricular tachycardia (Autosomal recessive inheritance)	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000271208.2 First in ClinVar: May 29, 2016 Last updated: May 29, 2016	Comment: show The c.940-1G>T variant in CASQ2 has not been previously reported in individuals with CPVT and was absent from large population studies. This variant occurs in t he invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Homozygous o r compound heterozygous variants in CASQ2 are strongly associated with CPVT and splice variants as well as loss-of-function variants are part of the pathogenic variant spectrum (Roux-Buisson 2011). In summary, although additional studies ar e required to fully establish its clinical significance, the c.940-1G>T variant is likely pathogenic for CPVT in an autosomal recessive manner. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Likely pathogenic (Sep 14, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Catecholaminergic polymorphic ventricular tachycardia 1 Catecholaminergic polymorphic ventricular tachycardia 2	Fulgent Genetics, Fulgent Genetics Accession: SCV002811536.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (May 20, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Catecholaminergic polymorphic ventricular tachycardia 1	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003472992.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 12386154‚ 16199547 Comment: show In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 228247). This variant has not been reported in the literature in individuals affected with CASQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the CASQ2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CASQ2 are known to be pathogenic (PMID: 12386154). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Apr 11, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Catecholaminergic polymorphic ventricular tachycardia 2	Genome-Nilou Lab Accession: SCV004050786.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Comment:

The c.940-1G>T variant in CASQ2 has not been previously reported in individuals with CPVT and was absent from large population studies. This variant occurs in t he invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Homozygous o r compound heterozygous variants in CASQ2 are strongly associated with CPVT and splice variants as well as loss-of-function variants are part of the pathogenic variant spectrum (Roux-Buisson 2011). In summary, although additional studies ar e required to fully establish its clinical significance, the c.940-1G>T variant is likely pathogenic for CPVT in an autosomal recessive manner.

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 228247). This variant has not been reported in the literature in individuals affected with CASQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the CASQ2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CASQ2 are known to be pathogenic (PMID: 12386154).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.	Postma AV	Circulation research	2002	PMID: 12386154

Text-mined citations for rs876657635 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 15, 2026