ClinVar Genomic variation as it relates to human health
NM_001232.4(CASQ2):c.97C>T (p.Arg33Ter)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001232.4(CASQ2):c.97C>T (p.Arg33Ter)
Variation ID: 41043 Accession: VCV000041043.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p13.1 1: 115768445 (GRCh38) [ NCBI UCSC ] 1: 116311066 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 3, 2013 Feb 14, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001232.4:c.97C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001223.2:p.Arg33Ter nonsense NC_000001.11:g.115768445G>A NC_000001.10:g.116311066G>A NG_008802.1:g.5361C>T LRG_404:g.5361C>T LRG_404t1:c.97C>T LRG_404p1:p.Arg33Ter - Protein change
- R33*
- Other names
- p.R33X:CGA>TGA
- Canonical SPDI
- NC_000001.11:115768444:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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CASQ2 | - | - |
GRCh38 GRCh37 |
689 | 730 |
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
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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. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Apr 11, 2023 | RCV000033942.13 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Feb 12, 2018 | RCV000170900.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 17, 2023 | RCV002513332.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 22, 2021 | RCV002496508.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV003318336.9 |
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
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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. |
More information
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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. |
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Likely pathogenic
(Feb 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000223457.11
First in ClinVar: May 23, 2015 Last updated: Apr 17, 2019 |
Comment:
The R33X likely pathogenic variant in the CASQ2 gene was initially reported in the heterozygous state in a female diagnosed with CPVT at 18 years-old … (more)
The R33X likely pathogenic variant in the CASQ2 gene was initially reported in the heterozygous state in a female diagnosed with CPVT at 18 years-old (Postma et al., 2002). Segregation analysis revealed that R33X was also present in five maternal relatives, two of whom experienced mild symptoms of CPVT during exercise. This variant was subsequently described in a heterozygous individual with near syncope; four of the proband's relatives were also found to harbor R33X, but only one of them had positive results on their stress test (Hayashi et al., 2012). The R33X variant has also been identified in conjunction with a second likely pathogenic CASQ2 variant in another individual referred for arrhythmia testing at GeneDx. In addition, R33X is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Moreover, other truncating variants in the CASQ2 gene have been reported in Human Gene Mutation Database in association with CPVT (Stenson et al., 2014).Therefore, while R33X in the CASQ2 gene is likely pathogenic, it may represent carrier status for an autosomal recessive CPVT. (less)
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Pathogenic
(Oct 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
Catecholaminergic polymorphic ventricular tachycardia 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002787444.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004048993.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Likely pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: research
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Long QT syndrome
Affected status: yes
Allele origin:
maternal
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Dept of Medical Biology, Uskudar University
Accession: SCV004021966.2
First in ClinVar: Jul 29, 2023 Last updated: Jan 26, 2024 |
Comment:
Criteria: PVS1_Strong, PM2
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Turkish
Geographic origin: Turkey
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Pathogenic
(Nov 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000760641.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg33*) in the CASQ2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg33*) in the CASQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASQ2 are known to be pathogenic (PMID: 12386154). This variant is present in population databases (rs397507556, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 12386154). ClinVar contains an entry for this variant (Variation ID: 41043). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925043.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
Variant CASQ2 p.Arg33* (c.97C>T), heterozygous in exon 1 (NM_001232.3, hg19 chr1-116311066-G-A) Seen in young adult with unexplained cardiac arrest, the only variant she has. SCICD … (more)
Variant CASQ2 p.Arg33* (c.97C>T), heterozygous in exon 1 (NM_001232.3, hg19 chr1-116311066-G-A) Seen in young adult with unexplained cardiac arrest, the only variant she has. SCICD classification Pathogenic (or recessive disease, variant of uncertain significance for autosomal dominant disease. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: unclear whether a heterozygous loss of function CASQ2 variant is sufficient to cause cardiac arrest. Gene-level evidence CASQ2 is a well recognized autosomal recessive CPVT gene. See below for details of possible autosomal dominant inheritance. Case data summary Reported in -1 unrelated case of CPVT with some segregation with a milder phenotype of polymorphic PVCs. -1 case of pediatric cardiac arrest/sudden death with another CASQ2 variant (frameshift). Please see below for a detailed review of case data. Experimental Data N/A Population Data Highest MAF in European (non-Finnish) population: 0.0008968% (1 allele, so wide error bars) CASQ2 gene-level evidence for heterozygous variants: A small portion of CPVT cases are caused by biallelic CASQ2 variants. The CASQ2 gene is typically associated with a recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT). Nevertheless, several clinical investigations suggest that a single CASQ2 mutation could represent a potential susceptibility factor for ventricular arrhythmias, including PVCs, bigeminy, or NSVT observed during exercise testing or adrenaline challenge (Roux-Buisson et al. 2011; de la Fuente et al. 2008; Postma et al. 2002). This is seen in a subset of heterozygous individuals from families in which a proband with CPVT has had 2 homozygous or compound heterozygous mutations in CASQ2. Liu et al. (2008) report a CPVT family in which they could find only one CASQ2 variant, although the article is in Chinese so was not reviewed. Knockout mice missing just one copy of CASQ2 also reportedly show more ventricular arrhythmias than wild-type mice in response to catecholamine challenge or programmed stimulation (Chopra et al. 2007). Gray et al (2016) published the most convincing clinical genetics data for autosomal dominant CASQ2-CPVT. They report a large Australian kindred with CPVT (including classic bidirectional ventricular tachycardia). A genome-wide approach (linkage and exome sequencing) identified linkage to the CASQ2 locus with a lod score of 3.01. Sequencing found a missense variant in CASQ2. They studied the variant with computer simulation methods previously used by their group to model CPVT and these data suggested haploinsufficiency likely was not the mechanisms of pathogenesis, making a dominant negative mechanism more likely. Postma et al (2002) reported a patient with the same variant as our patient (p.Arg133*), also in the heterozygous state. The proband had recurrent syncope after exercise starting at 11 years of age. At 18yo she was diagnosed with CPVT due to bidirectional VT on exercise test as well as numerous polymorphic PVCs on Holter. The paper notes she had a borderline QTc however in the table it is listed as 440 ms. Sequencing of LQTS genes was normal. Two carriers of the variant (maternal uncle and grandmother) had polymorphic PVCs on Holter. Three other carriers (mother, maternal aunt, maternal cousin) had normal exercise tests. I emailed the authors to ask for updated data on this family. Per ExAC, this gene is predicted to be tolerant to loss of function variation as of 12/22/2017 (pLI = 0), which fits with an autosomal recessive mode of inheritance. Case data: 1 case apparently heterozygous, CPVT - Postma et al (2002) - reviewed in gene level data above and included again here - Postma et al (2002) reported a patient with the same variant as our patient (p.Arg133*), also in the heterozygous state. The proband had recurrent syncope after exercise starting at 11 years of age. At 18yo she was diagnosed with CPVT due to bidirectional VT on exercise test as well as numerous polymorphic PVCs on Holter. The paper notes she had a borderline QTc however in the table it is listed as 440 ms. Sequencing of LQTS genes was normal. Two carriers of the variant (maternal uncle and grandmother) had polymorphic PVCs on Holter. Three other carriers (mother, maternal aunt, maternal cousin) had normal exercise tests. The pedigree is above. I emailed the authors to get and update and they shared the following: "She has remained asymptomatic since 1997 with a beta blocking treatment (nadolol 60 mg) and pacing because of bradycardia .No rythmic events since 1997. She still has polymorphic isolated PVCs on Holter monitorings." The paper does not note whether further analysis of the other allele was pursued. I have asked the authors. 1 case with two CASQ2 LoF variants, sudden death - internal lab data ClinVar - no case data reported. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Catecholaminergic polymorphic ventricular tachycardia 2
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000057872.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpText-mined citations for rs397507556 ...
HelpRecord last updated Mar 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.