ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.1526dup (p.Thr510fs)
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_170707.4(LMNA):c.1526dup (p.Thr510fs)
Variation ID: 48041 Accession: VCV000048041.13
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 1q22 1: 156137144-156137145 (GRCh38) [ NCBI UCSC ] 1: 156106935-156106936 (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 Oct 19, 2013 May 1, 2024 May 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.1526dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Thr510fs frameshift NM_005572.4:c.1526dup MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Thr510fs frameshift NM_001257374.3:c.1190dup NP_001244303.1:p.Thr398fs frameshift NM_001282624.2:c.1283dup NP_001269553.1:p.Thr429fs frameshift NM_001282625.2:c.1526dup NP_001269554.1:p.Thr510fs frameshift NM_001282626.2:c.1526dup NP_001269555.1:p.Thr510fs frameshift NM_170708.4:c.1526dup NP_733822.1:p.Thr510fs frameshift NC_000001.11:g.156137150dup NC_000001.10:g.156106941dup NG_008692.2:g.59578dup LRG_254:g.59578dup LRG_254t2:c.1526dup - Protein change
- T429fs, T398fs, T510fs
- Other names
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- Canonical SPDI
- NC_000001.11:156137144:CCCCCC:CCCCCCC
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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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LMNA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1839 | 2119 |
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 (1) |
no assertion criteria provided
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Dec 22, 2009 | RCV000041320.5 | |
Pathogenic (3) |
criteria provided, single submitter
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May 12, 2016 | RCV000057317.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 8, 2023 | RCV000476399.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2021 | RCV000618545.4 |
Submissions - Germline
Classification
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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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Pathogenic
(May 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000548851.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 48041). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 48041). This premature translational stop signal has been observed in individual(s) with LMNA-related diseases (PMID: 20848652, 23183350, 23702046, 24503780, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr510Tyrfs*42) in the LMNA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). (less)
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Pathogenic
(Nov 29, 2021)
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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: SCV000736322.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The c.1526dupC pathogenic mutation, located in coding exon 9 of the LMNA gene, results from a duplication of C at nucleotide position 1526, causing a … (more)
The c.1526dupC pathogenic mutation, located in coding exon 9 of the LMNA gene, results from a duplication of C at nucleotide position 1526, causing a translational frameshift with a predicted alternate stop codon (p.T510Yfs*42). This alteration has been reported in several dilated cardiomyopathy (DCM) cohorts and a muscular dystrophy cohort, and it has been shown to segregate with DCM and conduction disease in one family (Scharner J et al. Hum. Mutat. 2011;32:152-67; Saj M et al. BMC Med. Genet. 2013;14:55; Pugh TJ et al. Genet. Med. 2014;16:601-8; Walsh R et al. Genet. Med. 2017;19:192-203). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 12, 2016)
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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: SCV000234733.8
First in ClinVar: Jul 05, 2015 Last updated: Dec 06, 2016 |
Comment:
c.1526dupC: p.Thr510TyrfsX42 in exon 9 of the LMNA gene (NM_170707.2). The c.1526dupC pathogenic variant in the LMNA gene has been reported in one individual with … (more)
c.1526dupC: p.Thr510TyrfsX42 in exon 9 of the LMNA gene (NM_170707.2). The c.1526dupC pathogenic variant in the LMNA gene has been reported in one individual with DCM, reported as c.1526dupC or p.Thr510TyrfsX41 using alternate nomenclature (van Rijsingen IAW et al., 2013). The c.1526insC pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This pathogenic variant causes a shift in reading frame starting at codon Threonine 510, changing it to a Tyrosine, and creating a premature stop codon at position 42 of the new reading frame, denoted p.Thr510TyrfsX42. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift pathogenic variants in the LMNA gene have been reported in association with cardiomyopathy. Therefore, the presence of this pathogenic variant indicates an increased risk to develop a familial form of cardiomyopathy/laminopathy. However, other genetic and environmental factors influence disease expression and severity, and some pathogenic variant carriers may never become symptomatic. The variant is found in CARDIOMYOPATHY panel(s). (less)
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Likely pathogenic
(Dec 22, 2009)
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no assertion criteria provided
Method: clinical testing
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Primary dilated cardiomyopathy
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065013.4
First in ClinVar: May 03, 2013 Last updated: Jan 30, 2015 |
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000088431.1
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013 |
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not provided
(-)
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Flagged submission
flagged submission
Method: not provided
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000088430 appears to be redundant with SCV000088431.
(less)
Notes: SCV000088430 appears to
(...more)
Source: NCBI
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not provided
Affected status: not provided
Allele origin:
not provided
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Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000088430.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
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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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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 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
LMNA mutations in Polish patients with dilated cardiomyopathy: prevalence, clinical characteristics, and in vitro studies. | Saj M | BMC medical genetics | 2013 | PMID: 23702046 |
Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers. | van Rijsingen IA | European journal of heart failure | 2013 | PMID: 23183350 |
Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations. | Scharner J | Human mutation | 2011 | PMID: 20848652 |
Long-term outcome and risk stratification in dilated cardiolaminopathies. | Pasotti M | Journal of the American College of Cardiology | 2008 | PMID: 18926329 |
Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. | Parks SB | American heart journal | 2008 | PMID: 18585512 |
Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan. | Astejada MN | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2007 | PMID: 18646565 |
Gene symbol: LMNA. Disease: Cardiomyopathy, dilated, with conduction defect 1. | Arbustini Eloisa AE | Human genetics | 2005 | PMID: 16156025 |
Text-mined citations for rs58013325 ...
HelpRecord last updated Sep 29, 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.