ClinVar Genomic variation as it relates to human health
NM_002667.5(PLN):c.63_64dup (p.Gln22fs)
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.
Pathogenic(1); Likely pathogenic(3); 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.63_64dup (p.Gln22fs)
Variation ID: 202039 Accession: VCV000202039.13
- Type and length
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Duplication, 2 bp
- Location
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Cytogenetic: 6q22.31 6: 118558982-118558983 (GRCh38) [ NCBI UCSC ] 6: 118880145-118880146 (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 Jul 5, 2015 May 1, 2024 Dec 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001042475.3:c.1020+6545_1020+6546dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_002667.5:c.63_64dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002658.1:p.Gln22fs frameshift NM_001178035.2:c.1029+6545_1029+6546dup intron variant NM_002667.3:c.63_64dup NM_206921.3:c.1020+6545_1020+6546dup intron variant NC_000006.12:g.118558984_118558985dup NC_000006.11:g.118880147_118880148dup NG_009082.1:g.15706_15707dup NG_021248.1:g.156092_156093dup LRG_390:g.15706_15707dup LRG_390t1:c.63_64dup - Protein change
- Q22fs
- Other names
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- Canonical SPDI
- NC_000006.12:118558982:CTC:CTCTC
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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 |
85 | 279 | |
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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Likely pathogenic (2) |
criteria provided, single submitter
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May 11, 2022 | RCV000183819.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 6, 2016 | RCV000486215.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2019 | RCV000852566.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 30, 2023 | RCV001059490.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV002362944.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Dec 06, 2016)
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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: SCV000565761.2
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
The c.63_64dupTC variant of uncertain significance in the PLN gene has not been published as a pathogenic variant,nor has it been reported as a benign … (more)
The c.63_64dupTC variant of uncertain significance in the PLN gene has not been published as a pathogenic variant,nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, nor was it observedin the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations.The c.63_64dupTC variant causes a shift in reading frame starting at codon Glutamine 22, changing it to a Leucine,and creating a premature stop codon at position 19 of the new reading frame, denoted p.Gln22LeufsX19. This variantis expected to result in an abnormal, truncated protein product, as the last 31 amino acid residues are replaced with 18incorrect amino acid residues. Nevertheless, no downstream frameshift variants in the PLN gene have been reported inHGMD in association with cardiomyopathy (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.This result cannot be interpreted for diagnosis or used for family member screening at this time. (less)
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Likely pathogenic
(Jan 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995267.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 1
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Likely pathogenic
(May 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1P
Affected status: yes
Allele origin:
germline
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002506768.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
The homozygous c.63_64dup (p.Gln22LeufsTer19) variant identified in the PLN gene is the duplication of two nucleotides resulting in a frameshift ofthe protein at amino acid … (more)
The homozygous c.63_64dup (p.Gln22LeufsTer19) variant identified in the PLN gene is the duplication of two nucleotides resulting in a frameshift ofthe protein at amino acid 22/53 (exon 2/2). This variant is predicted to lead to the premature termination of the protein approximately 19 amino acids downstream. While this variant is not predicted to lead to nonsense mediated decay, several nonsense variants downstream have been reported in affected individuals, including the recurrent p.Leu39Ter variant [PMID:12639993; PMID:26535225]. This variant is found with low frequency in gnomAD (1 heterozygote, 0 homozygotes; allele frequency:6.57e-6) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported as both Likely Pathogenic and as a Variant of Uncertain Significance in ClinVar (VarID:202039), and has been identified in a single individual in the literature with hypertrophic cardiomyopathy (SuppTable 1A; [PMID:27532257]). The homozygous c.63_64dup (p.Gln22LeufsTer19) variant identified in the PLN gene is reported as Likely Pathogenic. (less)
Clinical Features:
Primary dilated cardiomyopathy (present)
Secondary finding: no
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Likely pathogenic
(May 11, 2022)
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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: SCV000901656.2 First in ClinVar: May 06, 2019 Last updated: Mar 11, 2023 |
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Pathogenic
(Dec 30, 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: SCV001224114.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln22Leufs*19) in the PLN gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Gln22Leufs*19) in the PLN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the PLN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 202039). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the PLN protein in which other variant(s) (p.Leu39*) have been determined to be pathogenic (PMID: 12639993, 17655857, 21167350, 25611685, 26535225). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Dec 11, 2023)
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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: SCV002657228.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.63_64dupTC variant, located in coding exon 1 of the PLN gene, results from a duplication of TC at nucleotide position 63, causing a translational … (more)
The c.63_64dupTC variant, located in coding exon 1 of the PLN gene, results from a duplication of TC at nucleotide position 63, causing a translational frameshift with a predicted alternate stop codon (p.Q22Lfs*19). This variant has been detected in an individual who underwent genetic testing for hypertrophic cardiomyopathy (HCM), and has also been detected in additional cohorts of individuals with HCM and other cardiomyopathies; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203; Smith E et al. J Am Heart Assoc. 2022 May;11(9):e024501; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of PLN has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 01, 2014)
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Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000236301 appears to be redundant with SCV000565761.
(less)
Notes: SCV000236301 appears to
(...more)
Source: NCBI
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Cardiomyopathy
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000236301.2
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
c.63_64dupTC: p.Gln22LeufsX19 (Q22LfsX19) in exon 2 of the PLN gene (NM_002667.3). The normal sequence with the bases that are duplicated in braces is: TGCC{TC}AACA.The c.63_64dupTC … (more)
c.63_64dupTC: p.Gln22LeufsX19 (Q22LfsX19) in exon 2 of the PLN gene (NM_002667.3). The normal sequence with the bases that are duplicated in braces is: TGCC{TC}AACA.The c.63_64dupTC variant in the PLN gene has not been reported to our knowledge. This variant causes a shift in reading frame starting at codon Glutamine 22, changing it to a Leucine, and creating a premature stop codon at position 19 of the new reading frame, denoted p.Gln22LeufsX19. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, no other frameshift mutations in the PLN gene have been reported in association with cardiomyopathy to date. With the clinical and molecular information available at this time, we cannot definitively determine if c.63_64dupTC in the PLN gene is a disease-causing mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s). (less)
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory. | Stava TT | European journal of preventive cardiology | 2022 | PMID: 35653365 |
Establishment of a Dedicated Inherited Cardiomyopathy Clinic: From Challenges to Improved Patients' Outcome. | Smith E | Journal of the American Heart Association | 2022 | PMID: 35470680 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Genetic modifiers to the PLN L39X mutation in a patient with DCM and sustained ventricular tachycardia? | Sanoudou D | Global cardiology science & practice | 2015 | PMID: 26535225 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing. | Landstrom AP | American heart journal | 2011 | PMID: 21167350 |
Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy. | Chiu C | Journal of molecular and cellular cardiology | 2007 | PMID: 17655857 |
Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. | Haghighi K | The Journal of clinical investigation | 2003 | PMID: 12639993 |
Text-mined citations for rs794729138 ...
HelpRecord last updated May 01, 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.