ClinVar Genomic variation as it relates to human health
NM_002667.5(PLN):c.25C>T (p.Arg9Cys)
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_002667.5(PLN):c.25C>T (p.Arg9Cys)
Variation ID: 13636 Accession: VCV000013636.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q22.31 6: 118558946 (GRCh38) [ NCBI UCSC ] 6: 118880109 (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 Apr 4, 2013 Feb 28, 2024 Dec 4, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001042475.3:c.1020+6583G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_002667.5:c.25C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002658.1:p.Arg9Cys missense NM_001178035.2:c.1029+6583G>A intron variant NM_206921.3:c.1020+6583G>A intron variant NC_000006.12:g.118558946C>T NC_000006.11:g.118880109C>T NG_009082.1:g.15668C>T NG_021248.1:g.156130G>A LRG_390:g.15668C>T LRG_390t1:c.25C>T P26678:p.Arg9Cys - Protein change
- R9C
- Other names
- p.R9C:CGC>TGC
- Canonical SPDI
- NC_000006.12:118558945:C:T
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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.
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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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CEP85L | - | - |
GRCh38 GRCh37 |
79 | 272 | |
PLN | - | - |
GRCh38 GRCh37 |
1 | 186 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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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Pathogenic (2) |
criteria provided, single submitter
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Dec 4, 2022 | RCV000014606.33 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 3, 2015 | RCV000211844.4 | |
Pathogenic (4) |
criteria provided, single submitter
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Aug 29, 2022 | RCV000183815.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 10, 2015 | RCV000769213.2 |
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
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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
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. |
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Pathogenic
(Dec 10, 2015)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900589.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Pathogenic
(Dec 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1P
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000638656.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PLN function (PMID: 12610310, 21282613, 22427649, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PLN function (PMID: 12610310, 21282613, 22427649, 22707725, 25593317). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 13636). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 12610310, 25928149, 26917049; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 9 of the PLN protein (p.Arg9Cys). (less)
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Pathogenic
(Jun 03, 2015)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204040.5
First in ClinVar: Jan 31, 2015 Last updated: Jun 03, 2016 |
Comment:
The p.Arg9Cys variant in PLN has been reported in 2 individuals with DCM and seg regated with disease in 7 affected relatives from 1 family, … (more)
The p.Arg9Cys variant in PLN has been reported in 2 individuals with DCM and seg regated with disease in 7 affected relatives from 1 family, including 3 obligate carriers (Schmitt 2003, Truszkowska 2015). Our laboratory has also identified o ne de novo occurrence of this variant in a child with ARVC. The p.Arg9Cys varian t was absent from large population studies, but is listed in dbSNP without frequ ency information (rs111033559). Transgenic mice expressing this variant develop DCM (Schmitt 2003, Schmitt 2009) and multiple functional studies support that th is variant has a severe impact on protein function (Gramolini 2007, Schmitt 2009 , Ha 2011, Ceholiski 2012a, Ceholiski 2012b, Abrol 2015). In summary, this varia nt meets our criteria to be classified as pathogenic for autosomal dominant DCM (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studie s and functional evidence. (less)
Number of individuals with the variant: 2
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Pathogenic
(Aug 29, 2022)
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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: SCV000236297.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate this variant leads to a complete loss of function in both … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate this variant leads to a complete loss of function in both humans and transgenic mouse models (Schmitt et al., 2003; Gramolini et al., 2008; Schmitt et al., 2009; Ha et al., 2011; Ceholski et al., 2012a; Ceholski et al., 2012b); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23308118, 25593317, 23989713, 23302633, 15765133, 26917049, 25928149, 33978571, 30638982, 33265898, 32755452, 34199719, 32393743, 30012515, 32603312, 31325238, 27239561, 22427649, 22707725, 21282613, 26183555, 28102477, 18056057, 17010801, 25651173, 19139388, 29119312, 29447731, 29752948, 31402444, 35297759, 12610310) (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955768.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967883.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Feb 15, 2011)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, DILATED, 1P
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034861.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In a 4-generation family segregating autosomal dominant dilated cardiomyopathy with heart failure (CMD1P; 609909), Schmitt et al. (2003) identified a C-to-T transition at nucleotide 25 … (more)
In a 4-generation family segregating autosomal dominant dilated cardiomyopathy with heart failure (CMD1P; 609909), Schmitt et al. (2003) identified a C-to-T transition at nucleotide 25 of the PLN gene, resulting in an arg9-to-cys (R9C) substitution in the cytosolic PLN domain. This mutation segregated absolutely with affected status in the family, occurred in a highly conserved residue, and was absent from more than 200 normal chromosomes. In the family, affected individuals had increased chamber dimensions and decreased contractile function at age 20 to 30 years, with progression to heart failure within 5 to 10 years after symptom onset. Congestive heart failure was severe in 12 individuals, necessitating cardiac transplantation in 4. The average age at death in affected individuals was 25.1 +/- 12.7 years. Using biochemical and biophysical techniques in vitro and in live cells, Ha et al. (2011) found that the R9C mutation led to stabilization of pentameric PLN due to disulfide bridge formation between the cytoplasmic domains of individual PLN(R9C) subunits. Stabilization of the PLN pentamer inhibited the dissociation of the pentamer into PLN monomers and promoted the formation of PLN(R9C) dimers, particularly under oxidative conditions. PKA (see 176911)-mediated phosphorylation of pentameric PLN(R9C) was significantly impaired due to this stabilization. (less)
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Pathogenic
(Aug 26, 2015)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280419.1
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg9Cys (c.25 C>T) The variant has been seen in at least one case of familial DCM with strong segregation and experimental data. Schmitt et al (2003) sequenced PLN in 20 individuals with familial DCM and found p.Arg9Cys in one of them. Five affected family members were available for genotyping and they all tested positive for this variant. Two of these individuals were fourth degree relatives to each other and several were third degree relatives to one another. The LOD score was 4.04. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 9 is completely conserved across species, and neighboring amino acids are highly conserved. The PLN gene encodes phospholamban, a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2 adenosine triphosphatase (SERCA2a) pump. Schmitt et al (2003) reported that transgenic mice with the p.Arg9Cys variant had heart failure and early death. In vitro studies showed constitutive inhibition of SERCA2a. There was a dominant negative effect in which the mutant protein trapped protein kinase A, which then failed to phosphorylate wildtype phospholamban. Calcium transients were prolonged and myocyte relaxation was delayed. In total the variant has not been seen in ~6600 published controls and individuals from publicly available population datasets. There is no variation at codon 9 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of February 8th, 2013). Note that this dataset does not match the patient's ancestry. Interestingly, there is actually only one nonsynonymous variant in PLN listed in the entire ESP dataset (p.Ile14Arg) and that is present in only 1 of ~6500 individuals. p.Arg9Cys is listed in 1000 genomes, but only in reference to the dbSNP entry (rs111033559) which in turn points to a clinical OMIM submission. Thus it is not noted as present in general population samples in either of these databases. The variant was not observed in the following published control samples: Schmitt et al (2003) did not observe the variant in 100 reportedly normal individuals. (less)
Number of individuals with the variant: 2
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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
HelpTitle | Author | Journal | Year | Link |
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A study in Polish patients with cardiomyopathy emphasizes pathogenicity of phospholamban (PLN) mutations at amino acid position 9 and low penetrance of heterozygous null PLN mutations. | Truszkowska GT | BMC medical genetics | 2015 | PMID: 25928149 |
Acute inotropic and lusitropic effects of cardiomyopathic R9C mutation of phospholamban. | Abrol N | The Journal of biological chemistry | 2015 | PMID: 25593317 |
Structure-function relation of phospholamban: modulation of channel activity as a potential regulator of SERCA activity. | Smeazzetto S | PloS one | 2013 | PMID: 23308118 |
Lethal, hereditary mutants of phospholamban elude phosphorylation by protein kinase A. | Ceholski DK | The Journal of biological chemistry | 2012 | PMID: 22707725 |
Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy. | Ceholski DK | The Journal of biological chemistry | 2012 | PMID: 22427649 |
Lethal Arg9Cys phospholamban mutation hinders Ca2+-ATPase regulation and phosphorylation by protein kinase A. | Ha KN | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 21282613 |
Alterations of phospholamban function can exhibit cardiotoxic effects independent of excessive sarcoplasmic reticulum Ca2+-ATPase inhibition. | Schmitt JP | Circulation | 2009 | PMID: 19139388 |
Comparative proteomics profiling of a phospholamban mutant mouse model of dilated cardiomyopathy reveals progressive intracellular stress responses. | Gramolini AO | Molecular & cellular proteomics : MCP | 2008 | PMID: 18056057 |
Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. | Schmitt JP | Science (New York, N.Y.) | 2003 | PMID: 12610310 |
Text-mined citations for rs111033559 ...
HelpRecord last updated Apr 06, 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.