ClinVar Genomic variation as it relates to human health
NM_002667.5(PLN):c.26G>A (p.Arg9His)
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.
Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002667.5(PLN):c.26G>A (p.Arg9His)
Variation ID: 202037 Accession: VCV000202037.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q22.31 6: 118558947 (GRCh38) [ NCBI UCSC ] 6: 118880110 (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 29, 2016 Feb 28, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001042475.3:c.1020+6582C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_002667.5:c.26G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002658.1:p.Arg9His missense NM_001178035.2:c.1029+6582C>T intron variant NM_206921.3:c.1020+6582C>T intron variant NC_000006.12:g.118558947G>A NC_000006.11:g.118880110G>A NG_009082.1:g.15669G>A NG_021248.1:g.156129C>T LRG_390:g.15669G>A LRG_390t1:c.26G>A P26678:p.Arg9His - Protein change
- R9H
- Other names
- p.R9H:CGC>CAC
- Canonical SPDI
- NC_000006.12:118558946: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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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Uncertain significance (1) |
criteria provided, single submitter
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Jan 24, 2013 | RCV000183816.2 | |
Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
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- | RCV001701633.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2023 | RCV001207506.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 30, 2022 | RCV002433818.1 |
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
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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
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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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Uncertain significance
(Jan 24, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000236298.8
First in ClinVar: Jul 05, 2015 Last updated: May 29, 2016 |
Comment:
p.Arg9His (CGC>CAC): c.26 G>A in exon 2 of the PLN gene (NM_002667.3). The Arg9His mutation in the PLN gene has been reported in one individual … (more)
p.Arg9His (CGC>CAC): c.26 G>A in exon 2 of the PLN gene (NM_002667.3). The Arg9His mutation in the PLN gene has been reported in one individual with DCM and was absent from 500 ethnically-matched control samples in this study (Medeiros A et al., 2011; Ceholski D et al., 2012). In addition, Arg9His was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although Arg9His results in a conservative amino acid substitution one hydrophilic residue for another, this substitution occurs at a position that is highly conserved across species. Mutations affecting this same residue, (Arg9Cys, Arg9Leu), have been reported in association with DCM (Schmitt J et al., 2003; Ha K et al., 2011; Ceholski D et al., 2012; Medeiros A et al., 2011), further supporting the functional importance of this residue. In silico analysis predicts Arg9His is damaging to the protein structure/function. Functional studies showed Arg9His results in complete loss of phosphorylation compared to wild-type, leading to sarcoplasmic reticulum calcium pump (SERCA) dysregulation, and consequent cardiovascular remodeling leading to heart failure (Ceholski D et al., 2012). In summary, Arg9His in the PLN gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s). (less)
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Uncertain significance
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002745382.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R9H variant (also known as c.26G>A), located in coding exon 1 of the PLN gene, results from a G to A substitution at nucleotide … (more)
The p.R9H variant (also known as c.26G>A), located in coding exon 1 of the PLN gene, results from a G to A substitution at nucleotide position 26. The arginine at codon 9 is replaced by histidine, an amino acid with highly similar properties. This variant was originally detected in an individual with dilated cardiomyopathy (DCM), as well as in his affected son and five unaffected first degree relatives (Medeiros A et al. Am Heart J, 2011 Dec;162:1088-1095.e1). In addition, this variant has been reported in hypertrophic cardiomyopathy (HCM) and DCM cohorts with limited clinical details provided (Lopes LR et al. Heart, 2015 Feb;101:294-301; Sousa A et al. Rev Port Cardiol (Engl Ed), 2019 Feb;38:129-139). Functional studies have shown that this variant affects PKA-mediated phosphorylation; however, the clinical impact is uncertain (Ceholski DK et al. J Biol Chem, 2012 May;287:16521-9; Ceholski DK et al. J Biol Chem, 2012 Aug;287:26596-605). Two other alterations at the same codon, p.R9C (c.25C>T) and p.R9L (c.26G>T), have also been described in individuals with DCM (Schmitt JP et al. Science, 2003 Feb;299:1410-3; Medeiros A et al. Am Heart J, 2011 Dec;162:1088-1095.e1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 13, 2023)
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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: SCV001378863.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 9 of the PLN protein (p.Arg9His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 9 of the PLN protein (p.Arg9His). This variant is present in population databases (rs754782171, gnomAD 0.005%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 22137083, 30871747). ClinVar contains an entry for this variant (Variation ID: 202037). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PLN function (PMID: 22707725, 25563649). This variant disrupts the p.Arg9 amino acid residue in PLN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12610310, 25928149, 26917049). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. (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: SCV001955974.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely 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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928505.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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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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Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy. | Qin J | eLife | 2022 | PMID: 35297759 |
Molecular characterization of Portuguese patients with dilated cardiomyopathy. | Sousa A | Revista portuguesa de cardiologia | 2019 | PMID: 30871747 |
The R9H phospholamban mutation is associated with highly penetrant dilated cardiomyopathy and sudden death in a spontaneous canine model. | Yost O | Gene | 2019 | PMID: 30794913 |
Effects of the Arg9Cys and Arg25Cys mutations on phospholamban's conformational equilibrium in membrane bilayers. | Nelson SED | Biochimica et biophysica acta. Biomembranes | 2018 | PMID: 29501609 |
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 |
Deception in simplicity: hereditary phospholamban mutations in dilated cardiomyopathy. | Young HS | Biochemistry and cell biology = Biochimie et biologie cellulaire | 2015 | PMID: 25563649 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
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 |
Mutations in the human phospholamban gene in patients with heart failure. | Medeiros A | American heart journal | 2011 | PMID: 22137083 |
Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. | Schmitt JP | Science (New York, N.Y.) | 2003 | PMID: 12610310 |
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Text-mined citations for rs754782171 ...
HelpRecord last updated Mar 05, 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.