ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.1072G>A (p.Glu358Lys)
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.1072G>A (p.Glu358Lys)
Variation ID: 14525 Accession: VCV000014525.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156136036 (GRCh38) [ NCBI UCSC ] 1: 156105827 (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 Feb 28, 2024 Sep 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.1072G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Glu358Lys missense NM_005572.4:c.1072G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Glu358Lys missense NM_001257374.3:c.736G>A NP_001244303.1:p.Glu246Lys missense NM_001282624.2:c.829G>A NP_001269553.1:p.Glu277Lys missense NM_001282625.2:c.1072G>A NP_001269554.1:p.Glu358Lys missense NM_001282626.2:c.1072G>A NP_001269555.1:p.Glu358Lys missense NM_170708.4:c.1072G>A NP_733822.1:p.Glu358Lys missense NC_000001.11:g.156136036G>A NC_000001.10:g.156105827G>A NG_008692.2:g.58464G>A LRG_254:g.58464G>A LRG_254t2:c.1072G>A P02545:p.Glu358Lys - Protein change
- E358K, E246K, E277K
- Other names
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- Canonical SPDI
- NC_000001.11:156136035: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.
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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 |
1826 | 2104 |
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 (1) |
no assertion criteria provided
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Aug 1, 2008 | RCV000015623.32 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 1, 2021 | RCV000015622.33 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 19, 2021 | RCV000057227.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 3, 2023 | RCV000470514.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000502108.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 12, 2021 | RCV001420791.2 |
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
Help
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
(Oct 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331050.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(May 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Emery-Dreifuss muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623153.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
Variant summary: LMNA c.1072G>A (p.Glu358Lys) results in a conservative amino acid change located in the rod domain (IPR039008) of the encoded protein sequence. Four of … (more)
Variant summary: LMNA c.1072G>A (p.Glu358Lys) results in a conservative amino acid change located in the rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251348 control chromosomes (gnomAD). c.1072G>A has been reported in the literature (usually as a de novo variant) in several individuals affected with typical- and atypical forms of Autosomal Dominant Emery-Dreifuss Muscular Dystrophy, with- or without cardiac involvement (see e.g. Mercuri_2004, Quijano-Roy_2008, van Rijsingen_2013, Pasqualin_2014, Fan_2021); in general most of the patients had muscle involvement, but the onset, severity, distribution of muscle weakness, and presence of associated features were highly variable. These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated abnormal intranuclear localization of the variant protein, which was associated with defective nuclear stability (Ostlund_2001, Zwerger_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 , and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000595623.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Pathogenic
(May 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001711959.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Emery-Dreifuss muscular dystrophy 2, autosomal dominant
Affected status: yes
Allele origin:
de novo
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976953.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM1, PM2, PP2, PP3, PP5
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Pathogenic
(Nov 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002017164.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 03, 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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Invitae
Accession: SCV000548856.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 358 of the LMNA protein (p.Glu358Lys). This missense change has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 10939567, 20980393, 21520333, 21632249, 23183350, 24508248). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 11792809, 23427149). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. ClinVar contains an entry for this variant (Variation ID: 14525). (less)
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Pathogenic
(Aug 01, 2008)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035888.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 15, 2022 |
Comment on evidence:
Mercuri et al. (2004) identified a de novo heterozygous 1072G-A transition in exon 5 of the LMNA gene, resulting in a glu358-to-lys (E358K) substitution, in … (more)
Mercuri et al. (2004) identified a de novo heterozygous 1072G-A transition in exon 5 of the LMNA gene, resulting in a glu358-to-lys (E358K) substitution, in 5 unrelated patients with muscular dystrophy. Three patients had the common phenotype of autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), 1 was diagnosed with early-onset limb-girdle muscular dystrophy type 1B (LGMD1B), which was reclassified as EDMD2 by Straub et al. (2018), and the last had had a more severe disorder consistent with congenital muscular dystrophy (613205). The mutation was not identified in 150 controls. The patient with LGMD1B also had cardiac conduction abnormalities, respiratory failure, and features of lipodystrophy (FPLD2; 151660). Mercuri et al. (2004) commented on the extreme phenotypic variability associated with this mutation. In 4 unrelated patients with LMNA-related congenital muscular dystrophy, Quijano-Roy et al. (2008) identified a de novo heterozygous mutation in exon 6 of the LMNA gene, resulting in a glu358-to-lys (E358K) substitution. Three patients presented before 1 year of age with hypotonia and later developed head drop with neck muscle weakness. There was delayed motor development with early loss of ambulation, distal limb contractures, axial and limb muscle weakness, respiratory insufficiency requiring mechanical ventilation, increased serum creatine kinase, and dystrophic changes on muscle biopsy. One patient developed ventricular tachycardia at age 20 years. The fourth patient with congenital LGMD1B had decreased fetal movements and presented at age 3 to 6 months with hypotonia, loss of head control, and delayed motor development. (less)
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Pathogenic
(Aug 01, 2008)
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no assertion criteria provided
Method: literature only
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EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035887.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 15, 2022 |
Comment on evidence:
Mercuri et al. (2004) identified a de novo heterozygous 1072G-A transition in exon 5 of the LMNA gene, resulting in a glu358-to-lys (E358K) substitution, in … (more)
Mercuri et al. (2004) identified a de novo heterozygous 1072G-A transition in exon 5 of the LMNA gene, resulting in a glu358-to-lys (E358K) substitution, in 5 unrelated patients with muscular dystrophy. Three patients had the common phenotype of autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), 1 was diagnosed with early-onset limb-girdle muscular dystrophy type 1B (LGMD1B), which was reclassified as EDMD2 by Straub et al. (2018), and the last had had a more severe disorder consistent with congenital muscular dystrophy (613205). The mutation was not identified in 150 controls. The patient with LGMD1B also had cardiac conduction abnormalities, respiratory failure, and features of lipodystrophy (FPLD2; 151660). Mercuri et al. (2004) commented on the extreme phenotypic variability associated with this mutation. In 4 unrelated patients with LMNA-related congenital muscular dystrophy, Quijano-Roy et al. (2008) identified a de novo heterozygous mutation in exon 6 of the LMNA gene, resulting in a glu358-to-lys (E358K) substitution. Three patients presented before 1 year of age with hypotonia and later developed head drop with neck muscle weakness. There was delayed motor development with early loss of ambulation, distal limb contractures, axial and limb muscle weakness, respiratory insufficiency requiring mechanical ventilation, increased serum creatine kinase, and dystrophic changes on muscle biopsy. One patient developed ventricular tachycardia at age 20 years. The fourth patient with congenital LGMD1B had decreased fetal movements and presented at age 3 to 6 months with hypotonia, loss of head control, and delayed motor development. (less)
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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: SCV000088340.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
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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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Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
Clinical spectrum and genetic variations of LMNA-related muscular dystrophies in a large cohort of Chinese patients. | Fan Y | Journal of medical genetics | 2021 | PMID: 32571898 |
229th ENMC international workshop: Limb girdle muscular dystrophies - Nomenclature and reformed classification Naarden, the Netherlands, 17-19 March 2017. | Straub V | Neuromuscular disorders : NMD | 2018 | PMID: 30055862 |
Congenital muscular dystrophy with dropped head linked to the LMNA gene in a Brazilian cohort. | Pasqualin LM | Pediatric neurology | 2014 | PMID: 24508248 |
Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling. | Zwerger M | Human molecular genetics | 2013 | PMID: 23427149 |
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 |
Inflammatory changes in infantile-onset LMNA-associated myopathy. | Komaki H | Neuromuscular disorders : NMD | 2011 | PMID: 21632249 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Specific phosphorylation of Ser458 of A-type lamins in LMNA-associated myopathy patients. | Mitsuhashi H | Journal of cell science | 2010 | PMID: 20980393 |
De novo LMNA mutations cause a new form of congenital muscular dystrophy. | Quijano-Roy S | Annals of neurology | 2008 | PMID: 18551513 |
Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene: from congenital onset with severe phenotype to milder classic Emery-Dreifuss variant. | Mercuri E | Archives of neurology | 2004 | PMID: 15148145 |
Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy. | Ostlund C | Journal of cell science | 2001 | PMID: 11792809 |
Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. | Bonne G | Annals of neurology | 2000 | PMID: 10939567 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA | - | - | - | - |
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Text-mined citations for rs60458016 ...
HelpRecord last updated Mar 17, 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.