ClinVar Genomic variation as it relates to human health
NM_002667.5(PLN):c.74G>A (p.Arg25His)
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.74G>A (p.Arg25His)
Variation ID: 410616 Accession: VCV000410616.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q22.31 6: 118558995 (GRCh38) [ NCBI UCSC ] 6: 118880158 (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 17, 2017 Feb 20, 2024 Nov 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001042475.3:c.1020+6534C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_002667.5:c.74G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002658.1:p.Arg25His missense NM_001178035.2:c.1029+6534C>T intron variant NM_206921.3:c.1020+6534C>T intron variant NC_000006.12:g.118558995G>A NC_000006.11:g.118880158G>A NG_009082.1:g.15717G>A NG_021248.1:g.156081C>T LRG_390:g.15717G>A LRG_390t1:c.74G>A - Protein change
- R25H
- Other names
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- Canonical SPDI
- NC_000006.12:118558994: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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
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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CEP85L | - | - |
GRCh38 GRCh37 |
80 | 273 | |
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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Nov 6, 2023 | RCV000460010.7 | |
Uncertain significance (2) |
criteria provided, single submitter
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Aug 5, 2022 | RCV000786193.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 13, 2022 | RCV002393144.1 |
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
(Oct 13, 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: SCV002670500.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R25H variant (also known as c.74G>A), located in coding exon 1 of the PLN gene, results from a G to A substitution at nucleotide … (more)
The p.R25H variant (also known as c.74G>A), located in coding exon 1 of the PLN gene, results from a G to A substitution at nucleotide position 74. The arginine at codon 25 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; (Harper AR et al. Nat Genet, 2021 02;53:135-142).). An alternate amino acid substitution at this codon, p.R25C, has been associated with a variety of cardiac phenotypes, including HCM, Brugada syndrome, and dilated cardiomyopathy (Lopes LR et al. Heart, 2015 Feb;101:294-301; Behr ER et al. Cardiovasc. Res., 2015 Jun;106:520-9; Liu GS et al. Cardiovasc. Res., 2015 Jul;107:164-74). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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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Uncertain significance
(Aug 05, 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: SCV001820406.4
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Walsh et al., 2017); Not observed at significant frequency in … (more)
Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Walsh et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28082330) (less)
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Uncertain significance
(Nov 06, 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: SCV000551437.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 25 of the PLN protein (p.Arg25His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 25 of the PLN protein (p.Arg25His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of PLN-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 410616). 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. This variant disrupts the p.Arg25 amino acid residue in PLN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25852082, 30847666; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 06, 2016)
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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: SCV000924901.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
PLN p.Arg25His Given the lack of case data we consider this variant to be of unknown significance and we do not feel it is suitable … (more)
PLN p.Arg25His Given the lack of case data we consider this variant to be of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in a patient with a clinical diagnosis of HCM and was diagnosed with Fabry disease by a very likely disease-causing variant on the HCM panel. Testing was done by Invitae. The PLN variant has not been reported in the literature (as of 6/13/2016). Another variant affecting codon 25 has been reported by Dr. Hershberger's group. Liu et al., 2015 identified the R25C variant in a family with DCM and prominent arrhythmias. The PLN R25C variant came from the maternal side of the pedigree and a LMNA variant (c.607 G>A, p.Glu203Lys) came from the paternal side (previously reported in Parks et al., 2009). These variants showed incomplete segregation. The PLN variant segregated with cardiac disease in four of seven family members and the LMNA variant segregated with cardiac disease in four of seven family members. One person had both variants and presented at 47 with sudden cardiac arrest, then was diagnosed with DCM. His mother (palpitatations at 47, PVCs at 57, DCM at 71) and two of his sisters (one with LV dilation since 51, NSVT and ICD and the other with DCM at 45, NSVT and ICD) had the PLN variant. His father (AFib at 65, EF 45% at 82), uncle (DCM at 62, conduction disease, SCD), and another sister (DCM at 39, VT and ICD) had the LMNA variant. Functional studies were consistent with impaired calcium handling, suggesting pathogenicity. The Invitae report notes that the "sequence change replaces arginine with histidine at codon 25 of the PLN protein (p.Arg25His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine...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, but these predictions have not been confirmed by published functional studies." There is no variation at codon 25 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/13/2016). The mean and median coverages at that site in ExAC are greater than 80x. Approximately 95% of individuals have 50x coverage. (less)
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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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Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Text-mined citations for rs1004405095 ...
HelpRecord last updated Feb 28, 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.