VCV000183230.5 - ClinVar

NM_006888.6(CALM1):c.389A>G (p.Asp130Gly)

Germline

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.

(3)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006888.6(CALM1):c.389A>G (p.Asp130Gly)

Variation ID: 183230 Accession: VCV000183230.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q32.11 14: 90404482 (GRCh38) [ NCBI UCSC ] 14: 90870826 (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	Jan 6, 2017	Feb 4, 2024	Nov 19, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_006888.6:c.389A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_008819.1:p.Asp130Gly	missense
NM_001363669.2:c.281A>G	NP_001350598.1:p.Asp94Gly	missense
NM_001363670.2:c.392A>G	NP_001350599.1:p.Asp131Gly	missense
NM_006888.4:c.389A>G
NC_000014.9:g.90404482A>G
NC_000014.8:g.90870826A>G
NG_013338.1:g.12500A>G
	P62158:p.Asp130Gly

... more HGVS ... less HGVS

Protein change

D130G, D94G, D131G

Other names

Canonical SPDI

NC_000014.9:90404481:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

Links

ClinGen: CA186013 UniProtKB: P62158#VAR_073278 OMIM: 114180.0003 dbSNP: rs730882252 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 23388215 Fig. 3 to determine the location of this allele on the current reference sequence.

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.
CALM1		No evidence available	No evidence available	GRCh38 GRCh37	101	168
LOC126862021	-	-	-	GRCh38	-	39

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.
Long QT syndrome 14	Pathogenic (2)	criteria provided, single submitter	Jul 22, 2020	RCV000162062.5
not provided	Likely pathogenic (1)	criteria provided, single submitter	Nov 19, 2020	RCV001781506.4

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.	More information 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.
Pathogenic (Jul 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Long QT syndrome 14 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV001426216.1 First in ClinVar: Aug 02, 2020 Last updated: Aug 02, 2020	Publications: PubMed (3) PubMed: 23388215‚ 26164367‚ 27165696 Comment: This variant is interpreted as pathogenic for Long QT syndrome 14, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely … (more) This variant is interpreted as pathogenic for Long QT syndrome 14, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Assumed de novo, but no confirmation of paternity and maternity (PM6); Well-established functional studies show a deleterious effect (PS3); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1). (less)
Likely pathogenic (Nov 19, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002025047.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 05, 2013)	no assertion criteria provided Method: literature only	LONG QT SYNDROME 14 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000212095.3 First in ClinVar: Mar 04, 2015 Last updated: Jan 06, 2017	Publications: PubMed (1) PubMed: 23388215 Comment on evidence: In an Italian girl and a Greek boy with markedly prolonged QTc intervals and early-onset life-threatening ventricular arrhythmias (LQT14; 616247), Crotti et al. (2013) identified … (more) In an Italian girl and a Greek boy with markedly prolonged QTc intervals and early-onset life-threatening ventricular arrhythmias (LQT14; 616247), Crotti et al. (2013) identified heterozygosity for an A-to-G transition in the CALM1 gene, resulting in an asp130-to-gly (D130G) substitution at a highly conserved residue in the EF-hand domain IV. The mutation, which occurred de novo in both patients, was not found in 1,800 white European controls or in the dbSNP (build 130), 1000 Genomes Project, Exome Variant Server, or Helmholtz databases. Functional analysis demonstrated a 53-fold reduction in calcium affinity with the D130G mutant compared to wildtype calmodulin. (less)

Comment:

This variant is interpreted as pathogenic for Long QT syndrome 14, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Assumed de novo, but no confirmation of paternity and maternity (PM6); Well-established functional studies show a deleterious effect (PS3); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1).

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Arrhythmogenic calmodulin mutations impede activation of small-conductance calcium-activated potassium current.	Yu CC	Heart rhythm	2016	PMID: 27165696
Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease.	Vassilakopoulou V	Biochimica et biophysica acta	2015	PMID: 26164367
Calmodulin mutations associated with recurrent cardiac arrest in infants.	Crotti L	Circulation	2013	PMID: 23388215

Text-mined citations for rs730882252 ...

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 Mar 17, 2024

ClinVar Genomic variation as it relates to human health

NM_006888.6(CALM1):c.389A>G (p.Asp130Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs730882252 ...