ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu)
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.
Uncertain significance(10); Benign(1); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu)
Variation ID: 14517 Accession: VCV000014517.79
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156138507 (GRCh38) [ NCBI UCSC ] 1: 156108298 (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 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.1718C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Ser573Leu missense NM_001257374.3:c.1382C>T NP_001244303.1:p.Ser461Leu missense NM_001282626.2:c.1718C>T NP_001269555.1:p.Ser573Leu missense NM_170708.4:c.1628C>T NP_733822.1:p.Ser543Leu missense NC_000001.11:g.156138507C>T NC_000001.10:g.156108298C>T NG_008692.2:g.60935C>T LRG_254:g.60935C>T LRG_254t2:c.1718C>T P02545:p.Ser573Leu - Protein change
- S573L, S543L, S461L
- Other names
- chr1-156138507-C-T
- Canonical SPDI
- NC_000001.11:156138506:C:T
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00011
The Genome Aggregation Database (gnomAD) 0.00011
The Genome Aggregation Database (gnomAD), exomes 0.00015
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
1816 | 2093 |
Conditions - Germline
Condition
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (2) |
no assertion criteria provided
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Feb 1, 2007 | RCV000015612.31 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 1, 2007 | RCV000015613.29 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 1, 2007 | RCV000015614.25 | |
Conflicting interpretations of pathogenicity (10) |
criteria provided, conflicting classifications
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Feb 1, 2023 | RCV000057351.23 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 28, 2022 | RCV000041329.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 5, 2023 | RCV001188887.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 20, 2021 | RCV002221478.1 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 15, 2022 | RCV002509159.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2024 | RCV000617932.4 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV000653881.5 | |
Benign (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001248900.3 | |
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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
Help
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
Help
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
(Nov 14, 2017)
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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: SCV000700905.2
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Likely benign
(Jun 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001476537.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Uncertain significance
(Dec 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065022.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2021 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. The p.Ser573Leu variant in LMNA has been identified in individuals across multiple phenotypes: in the heterozygous state … (more)
Variant classified as Uncertain Significance - Favor Benign. The p.Ser573Leu variant in LMNA has been identified in individuals across multiple phenotypes: in the heterozygous state in 5 individuals with DCM, including 1 who had likely pathogenic variant in another gene that could explain their disease (Taylor 2003 PMID:12628721, Pasotti 2008 PMID:18926329, Dal Ferro 2017 PMID: 28416588, LMM data) and segregated with disease in 3 affected relatives from 2 families (Pasotti 2008, PMID:18926329). It has also been reported in 2 individuals with HCM (LMM data), 1 individual with Brugada syndrome (Proost 2017 PMID :28341588), 5 individuals with Limb-Girdle or Emery-Dreifuss muscular dystrophy (Benedetti 2007 PMID: 17377071, Bernasconi 2018 PMID: 29693488), and 1 individual with familial partial lipodystrophy (Lanktree 2007 PMID: 17250669). In the homozygous state, this variant has been reported in an individual with arthropathy, tendinous calcinosis, and progeroid features (Van Esch 2006 PMID: 16278265). This variant segregated with DCM in 3 affected relatives from 2 families (Pasotti 2008, PMID:18926329). In addition, this variant has also been reported by other clinical laboratories in ClinVar (Variation ID 14517) and has also been identified in 0.04% (4/10102) of Ashekanzi Jewish chromosomes, 0.04% (13/35168) of Latino chromosomes, and in 0.01% (14/121150) of European chromosomes, including one homozygote, by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant does not impact protein function (Nitta 2006 PMID 16809772, Van Tienen PMID 30420677); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency in the general population suggests that it is more likely to be benign. ACMG/AMP Criteria Applied: PP1, BS1. (less)
Number of individuals with the variant: 5
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Uncertain significance
(Nov 11, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715575.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Uncertain significance
(Aug 26, 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: SCV000491119.3
First in ClinVar: Oct 19, 2013 Last updated: Mar 04, 2023 |
Comment:
Reported in the heterozygous state in individuals with DCM, HCM, arrhythmia, familial partial lipodystrophy subtype 2, and in a patient with a Limb-girdle muscular dystrophy … (more)
Reported in the heterozygous state in individuals with DCM, HCM, arrhythmia, familial partial lipodystrophy subtype 2, and in a patient with a Limb-girdle muscular dystrophy phenotype with no cardiac involvement (Pasotti et al., 2008; Francisco et al., 2017; Taylor et al., 2003; Lanktree et al., 2007; Benedetti et al., 2007; Zhang et al., 2016; Proost et al., 2017; van Tienen, 2019; Quaio et al., 2020; Gigli et al., 2019); Reported previously in a patient with HCM who also had a variant reported in MYL2 that was thought to be responsible for the phenotype; complete segregation information was unavailable (De Bortoli et al., 2020); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 14517; ClinVar); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one homozygous individual in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24846508, 28341588, 19875478, 18926329, 30420677, 17377071, 24503780, 27707468, 16636128, 18031308, 12628721, 28874324, 28663758, 28416588, 29800922, 29764566, 16809772, 32799420, 32746448, 10939567, 15475483, 31525256, 31514951, 33258288, 17250669, 33916827, 16278265, 32004434, 35535697, ZhaoY2022, 32616434, 29693488) (less)
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Uncertain significance
(Sep 22, 2022)
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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: SCV003814686.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Apr 05, 2023)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001356059.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with leucine at codon 573 of the lamin A protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces serine with leucine at codon 573 of the lamin A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant can restore LMNA protein function in LMNA-deficient fibroblasts (PMID: 16809772), and does not change lamina organization or the interaction with chromatin (Banerjee et al. 2020, https://doi.org/10.1101/2020.05.01.071803). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 12628721, 18926329, 28416588, 32616434, 32746448, 35026164), in an individual affected with cardiac arrhythmia (PMID: 28341588), in an individual with a complex phenotype including hypertrophic cardiomyopathy, left ventricular outflow tract obstruction and metabolic syndrome (PMID: 28874324), in an individual affected with Brugada syndrome (PMID: 35026164), and in an individual affected with hypertrophic cardiomyopathy who also carried a pathogenic variant in the MYL2 gene that could explain the observed phenotype (PMID: 32004434). This variant has also been reported in an individual with lipodystrophy (PMID: 17250669), in an individual affected with limb-girdle muscular dystrophy without cardiac involvement (PMID: 17377071), in an individual with progeroid features with no evidence of cardiomyopathy (PMID: 16278265), and in an individual affected with type 2 familial partial lipodystrophy (PMID: 33916827). However, this variant has also been identified in 38/271142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Jan 26, 2024)
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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: SCV000775771.5
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
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Uncertain significance
(Feb 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004124993.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
LMNA: PP1
Number of individuals with the variant: 1
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Uncertain significance
(Jan 12, 2024)
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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: SCV000738025.6
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.S573L variant (also known as c.1718C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide … (more)
The p.S573L variant (also known as c.1718C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide position 1718. The serine at codon 573 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with diseases on the laminopathy spectrum, including individuals with dilated cardiomyopathy (DCM), at least one of whom also had variants in other cardiac-related genes (Taylor MR et al. J. Am. Coll. Cardiol., 2003 Mar;41:771-80; Pasotti M et al. J. Am. Coll. Cardiol., 2008 Oct;52:1250-60; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Dal Ferro M et al. Heart, 2017 11;103:1704-1710), as well as individuals with unspecified primary electrical disease (Proost D et al. J Mol Diagn, 2017 05;19:445-459), familial partial leukodystrophy type 2 (Lanktree M et al. Clin. Genet., 2007 Feb;71:183-6), limb-girdle dystrophy (Benedetti S et al. Neurology, 2007 Sep;69:1285-92; Bernasconi P et al. Nucleus, 2018 01;9:292-304), and Emery-Dreifuss muscular dystrophy (Bernasconi P et al. Nucleus, 2018 01;9:292-304). This variant was also detected as heterozygous in an individual with hypertrophic cardiomyopathy (HCM) and metabolic syndrome (Francisco ARG et al. Rev Port Cardiol, 2017 Sep;36:669.e1-669.e4). In addition, this variant was described as homozygous in an individual with a novel arthropathy phenotype demonstrating progeroid features, generalized lipodystrophy, and sclerodermatous skin (Van Esch H et al. J. Clin. Endocrinol. Metab., 2006 Feb;91:517-21); this patient's heterozygous son and presumed obligate carrier mother were unaffected with no reported cardiac findings. This variant has also been detected in cohorts not selected for the presence of LMNA-related disease; however, details were limited (Kasak L et al. Hum Reprod. 2022 Jun;37(7):1652-1663; Quaio CRDC et al. Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):955-964). In one experimental study, this alteration was found to restore responsiveness in LMNA-deficient fibroblasts (Nitta RT et al. Mol Cell Biol, 2006 Jul;26:5360-72). This amino acid position is not well 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)
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Uncertain significance
(Jul 20, 2021)
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criteria provided, single submitter
Method: research
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Charcot-Marie-Tooth disease type 2B1
Affected status: yes
Allele origin:
germline
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Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo
Accession: SCV001977120.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
The c.1718C> T (p.Ser573Leu) variant in the LMNA gene has been described in the literature as both heterozygous and homozygous in several individuals with a … (more)
The c.1718C> T (p.Ser573Leu) variant in the LMNA gene has been described in the literature as both heterozygous and homozygous in several individuals with a variety of phenotypes (PMID: 16278265; PMID: 12628721; PMID: 28874324; PMID: 18926329; PMID: 17250669; PMID: 28416588; PMID: 29693488; PMID: 30420677; PMID: 16809772). This variant is deposited in the ClinVar, but there is a conflict of interpretation (Variation ID: 14517), 1 star. This variant, also known as p.Ser543Leu, replaces Serine with Leucine at codon 573 (543) of the LMNA protein that is highly conserved across different species. This variant is present in the gnomAD (rs60890628; 0.01401e-2) and ABraOM (rs60890628; 0.000427) population database at reasonable frequency, including 1 homozygote. Our lab found it once, in heterozygous, in a 10-years-old male with a mild CMT2 phenotype and mild diffuse muscle weakness, predominantly distal, but also affecting the face who also have a variant, classified as likely pathogenic, in the EMD gene (ClinVar ID: SCV001976635). Interestingly, a study published in 2007 described a single family with high intrafamilial phenotypic heterogeneity that had variants in both genes (LMNA + EMD) and demonstrated that alterations in these two genes likely have a synergistic effect on both the phenotype and expression of laminin proteins A and C (PMID: 17536044). However, we do not know its real effect on our patient's phenotype. Therefore, it has been classified as a variant of uncertain significance (VUS). (less)
Number of individuals with the variant: 1
Geographic origin: Brazil
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Benign
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Familial partial lipodystrophy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422587.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Ser573Leu variant in LMNA has been reported in 1 European individual with familial partial lipodystrophy (PMID: 17250669), but has been identified in 0.04% (4/10102) … (more)
The p.Ser573Leu variant in LMNA has been reported in 1 European individual with familial partial lipodystrophy (PMID: 17250669), but has been identified in 0.04% (4/10102) of Ashkenazi Jewish chromosomes and other populations at slightly lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs60890628). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 14517). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as benign for familial partial lipodystrophy in an autosomal dominant manner based on its frequency in the general population. ACMG/AMP Criteria applied: BA1 (Richards 2015). (less)
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Uncertain significance
(Apr 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511981.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: LMNA c.1718C>T (p.Ser573Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: LMNA c.1718C>T (p.Ser573Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 239760 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in LMNA causing Cardiomyopathy (0.00015 vs 0.00025), allowing no conclusion about variant significance. c.1718C>T has been reported in the literature in individuals affected with different phenotypes including, dilated cardiomyopathy (Taylor_2003, Pasotti_2008, Pugh_2014, Dal Ferro_2017, Burstein_2021), hypertrophic cardiomyopathy (Francisco_2017), long QT syndrome (van Tienen_2019), limb-girdle muscular dystrophy (Benedetti_2007, Bernasconi_2018), familial partial lipodystrophy (Lanktree_2007), and Emery-Dreifuss muscular dystrophy (Bernasconi_2018), but it was also reported in unaffected individuals (e.g. Taylor_2003, Van Esch_2006). Furthermore, the variant was reported in a homozygous patient affected with arthropathy, tendinous calcinosis, and progeroid features (Van Esch_2006). These reports do not provide unequivocal conclusions about association of the variant with disease. At least one co-occurrence with a pathogenic variant has been reported in a patient affected with dilated cardiomyopathy (TTN c.49511delG, p.Gly16504GlufsX12; Pugh_2014). Experimental evidence demonstrated the variant can restore protein function in LMNA-deficient cells and generally confer normal nuclear morphology (Nitta_2006, van Tienen_2019). However, this evidence does not allow convincing conclusions about the variant effect. Ten ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments: uncertain significance (n=7), benign/likely (n=2), likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(-)
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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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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979124.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Uncertain significance
(-)
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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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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036352.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(Feb 01, 2007)
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no assertion criteria provided
Method: literature only
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MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035878.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 19, 2022 |
Comment on evidence:
In a 50-year-old Italian woman with sporadic dilated cardiomyopathy with conduction defects (CMD1A; 115200), Taylor et al. (2003) identified heterozygosity for a 1718C-T transition in … (more)
In a 50-year-old Italian woman with sporadic dilated cardiomyopathy with conduction defects (CMD1A; 115200), Taylor et al. (2003) identified heterozygosity for a 1718C-T transition in exon 11 of the LMNA gene, resulting in a ser573-to-leu substitution at a highly conserved residue, predicted to affect the carboxyl tail of the lamin A isoform. The mutation was not found in the proband's 2 unaffected offspring or in 300 control chromosomes, but her unaffected 60-year-old sister also carried the mutation. Van Esch et al. (2006) analyzed the LMNA gene in a 44-year-old male of European descent with arthropathy, tendinous calcifications, and a progeroid appearance (see 248370) and identified homozygosity for the S573L mutation. Progeroid features included a small pinched nose, small lips, micrognathia with crowded teeth, cataract, and alopecia. He also had generalized lipodystrophy, and sclerodermatous skin. The arthropathy affected predominantly the distal femora and proximal tibia in the knee with tendinous calcifications. However, he had normal clavicles and no evidence of acroosteolysis. The authors concluded that he had a novel phenotype. The patient's unaffected 15-year-old son was heterozygous for the mutation, which was not found in 450 control chromosomes. The authors noted that the patient had no evidence of cardiomyopathy and his 70-year-old mother, an obligate heterozygote, had no known cardiac problems. In a 75-year-old European male with partial lipodystrophy (FPLD2; 151660), Lanktree et al. (2007) identified heterozygosity for the S573L mutation in the LMNA gene. (less)
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Pathogenic
(Feb 01, 2007)
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no assertion criteria provided
Method: literature only
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LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035879.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 19, 2022 |
Comment on evidence:
In a 50-year-old Italian woman with sporadic dilated cardiomyopathy with conduction defects (CMD1A; 115200), Taylor et al. (2003) identified heterozygosity for a 1718C-T transition in … (more)
In a 50-year-old Italian woman with sporadic dilated cardiomyopathy with conduction defects (CMD1A; 115200), Taylor et al. (2003) identified heterozygosity for a 1718C-T transition in exon 11 of the LMNA gene, resulting in a ser573-to-leu substitution at a highly conserved residue, predicted to affect the carboxyl tail of the lamin A isoform. The mutation was not found in the proband's 2 unaffected offspring or in 300 control chromosomes, but her unaffected 60-year-old sister also carried the mutation. Van Esch et al. (2006) analyzed the LMNA gene in a 44-year-old male of European descent with arthropathy, tendinous calcifications, and a progeroid appearance (see 248370) and identified homozygosity for the S573L mutation. Progeroid features included a small pinched nose, small lips, micrognathia with crowded teeth, cataract, and alopecia. He also had generalized lipodystrophy, and sclerodermatous skin. The arthropathy affected predominantly the distal femora and proximal tibia in the knee with tendinous calcifications. However, he had normal clavicles and no evidence of acroosteolysis. The authors concluded that he had a novel phenotype. The patient's unaffected 15-year-old son was heterozygous for the mutation, which was not found in 450 control chromosomes. The authors noted that the patient had no evidence of cardiomyopathy and his 70-year-old mother, an obligate heterozygote, had no known cardiac problems. In a 75-year-old European male with partial lipodystrophy (FPLD2; 151660), Lanktree et al. (2007) identified heterozygosity for the S573L mutation in the LMNA gene. (less)
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Pathogenic
(Feb 01, 2007)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, DILATED, 1A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035877.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 19, 2022 |
Comment on evidence:
In a 50-year-old Italian woman with sporadic dilated cardiomyopathy with conduction defects (CMD1A; 115200), Taylor et al. (2003) identified heterozygosity for a 1718C-T transition in … (more)
In a 50-year-old Italian woman with sporadic dilated cardiomyopathy with conduction defects (CMD1A; 115200), Taylor et al. (2003) identified heterozygosity for a 1718C-T transition in exon 11 of the LMNA gene, resulting in a ser573-to-leu substitution at a highly conserved residue, predicted to affect the carboxyl tail of the lamin A isoform. The mutation was not found in the proband's 2 unaffected offspring or in 300 control chromosomes, but her unaffected 60-year-old sister also carried the mutation. Van Esch et al. (2006) analyzed the LMNA gene in a 44-year-old male of European descent with arthropathy, tendinous calcifications, and a progeroid appearance (see 248370) and identified homozygosity for the S573L mutation. Progeroid features included a small pinched nose, small lips, micrognathia with crowded teeth, cataract, and alopecia. He also had generalized lipodystrophy, and sclerodermatous skin. The arthropathy affected predominantly the distal femora and proximal tibia in the knee with tendinous calcifications. However, he had normal clavicles and no evidence of acroosteolysis. The authors concluded that he had a novel phenotype. The patient's unaffected 15-year-old son was heterozygous for the mutation, which was not found in 450 control chromosomes. The authors noted that the patient had no evidence of cardiomyopathy and his 70-year-old mother, an obligate heterozygote, had no known cardiac problems. In a 75-year-old European male with partial lipodystrophy (FPLD2; 151660), Lanktree et al. (2007) identified heterozygosity for the S573L mutation in the LMNA gene. (less)
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Pathogenic
(Apr 15, 2022)
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no assertion criteria provided
Method: clinical testing
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Congenital muscular dystrophy due to LMNA mutation
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Department of Medical Genetics, National Institute of Health
Accession: SCV002547317.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
We report the case of a 7-month-old Moroccan male child presenting with congenital hypotonia, muscle weakness, dropped head syndrome, and normal heart function. In the … (more)
We report the case of a 7-month-old Moroccan male child presenting with congenital hypotonia, muscle weakness, dropped head syndrome, and normal heart function. In the literature, the NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu) (dbSNP: rs60890628) variant in exon 11 of the LMNA gene has been identified in individuals across multiple forms: In the heterozygous state with dilated cardiomyopathy (Taylor 2003 PMID:12628721, Pasotti 2008 PMID:18926329, Dal Ferro 2017 PMID: 28416588, Burstein 2021 PMID: 32746448), hypertrophic cardiomyopathy (Francisco 2017 PMID: 28874324). Moreover, patients with Limb-Girdle or Emery-Dreifuss muscular dystrophy (Benedetti 2007 PMID: 17377071, Bernasconi 2018 PMID: 29693488), and familial partial lipodystrophy (Lanktree 2007 PMID: 17250669) were also reported. In the homozygous state, this variant has been reported in an individual with arthropathy, tendinous calcinosis, and progeroid features (Van Esch 2006 PMID: 16278265) with no cardiac involvement. The heterozygous missense c.1718C>T variant was not found in 138 Moroccan clinical exomes (in-house database), and It was classified as a pathogenic variant with PP5, PM1, PM2, PP2, PP3, and PS2 rules according to the recommendations of ACMG/AMP. We report for the first time a new phenotype associated with a de novo variant in exon 11 of the LMNA gene: Congenital muscular dystrophy. We assume that it is a strong candidate variation responsible for the phenotype in our patient. (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Moroccan
Geographic origin: Morocco
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Uncertain significance
(-)
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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: SCV001979692.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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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: SCV000088464.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
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Likely pathogenic
(May 01, 2021)
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Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Dilated cardiomyopathy 1A
Affected status: unknown
Allele origin:
unknown
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Laan Lab, Human Genetics Research Group, University of Tartu
Accession: SCV002538608.1
First in ClinVar: Jul 01, 2022 Last updated: Jul 01, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Non-obstructive azoospermia (present)
Secondary finding: yes
Method: exome sequencing
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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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Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. | Kasak L | Human reproduction (Oxford, England) | 2022 | PMID: 35535697 |
The genetic architecture of pediatric cardiomyopathy. | Ware SM | American journal of human genetics | 2022 | PMID: 35026164 |
Variable Expressivity and Allelic Heterogeneity in Type 2 Familial Partial Lipodystrophy: The p.(Thr528Met) LMNA Variant. | Araújo-Vilar D | Journal of clinical medicine | 2021 | PMID: 33916827 |
Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. | Burstein DS | Pediatric research | 2021 | PMID: 32746448 |
Risk predictors in a Spanish cohort with cardiac laminopathies. The REDLAMINA registry. | Barriales-Villa R | Revista espanola de cardiologia (English ed.) | 2021 | PMID: 32616434 |
Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases. | Quaio CRDC | American journal of medical genetics. Part C, Seminars in medical genetics | 2020 | PMID: 33258288 |
Novel Missense Variant in MYL2 Gene Associated With Hypertrophic Cardiomyopathy Showing High Incidence of Restrictive Physiology. | De Bortoli M | Circulation. Genomic and precision medicine | 2020 | PMID: 32004434 |
Using linkage studies combined with whole-exome sequencing to identify novel candidate genes for familial colorectal cancer. | Toma C | International journal of cancer | 2020 | PMID: 31525256 |
A genome-first approach to aggregating rare genetic variants in LMNA for association with electronic health record phenotypes. | Park J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31383942 |
Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. | Gigli M | Journal of the American College of Cardiology | 2019 | PMID: 31514951 |
Assessment of fibroblast nuclear morphology aids interpretation of LMNA variants. | van Tienen FHJ | European journal of human genetics : EJHG | 2019 | PMID: 30420677 |
Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes. | Bernasconi P | Nucleus (Austin, Tex.) | 2018 | PMID: 29693488 |
Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. | Francisco ARG | Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology | 2017 | PMID: 28874324 |
LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes. | Florwick A | Frontiers in genetics | 2017 | PMID: 28663758 |
Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy. | Dal Ferro M | Heart (British Cardiac Society) | 2017 | PMID: 28416588 |
Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. | Proost D | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28341588 |
Does Sudden Unexplained Nocturnal Death Syndrome Remain the Autopsy-Negative Disorder: A Gross, Microscopic, and Molecular Autopsy Investigation in Southern China. | Zhang L | Mayo Clinic proceedings | 2016 | PMID: 27707468 |
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 |
Dupuytren's Contracture Cosegregation with Limb-Girdle Muscle Dystrophy. | Lace B | Case reports in neurological medicine | 2013 | PMID: 24024053 |
Quantitative expression of the mutated lamin A/C gene in patients with cardiolaminopathy. | Narula N | Journal of the American College of Cardiology | 2012 | PMID: 23062543 |
Long-term outcome and risk stratification in dilated cardiolaminopathies. | Pasotti M | Journal of the American College of Cardiology | 2008 | PMID: 18926329 |
Multitissular involvement in a family with LMNA and EMD mutations: Role of digenic mechanism? | Ben Yaou R | Neurology | 2007 | PMID: 17536044 |
Phenotypic clustering of lamin A/C mutations in neuromuscular patients. | Benedetti S | Neurology | 2007 | PMID: 17377071 |
Novel LMNA mutations seen in patients with familial partial lipodystrophy subtype 2 (FPLD2; MIM 151660). | Lanktree M | Clinical genetics | 2007 | PMID: 17250669 |
Stabilization of the retinoblastoma protein by A-type nuclear lamins is required for INK4A-mediated cell cycle arrest. | Nitta RT | Molecular and cellular biology | 2006 | PMID: 16809772 |
A homozygous mutation in the lamin A/C gene associated with a novel syndrome of arthropathy, tendinous calcinosis, and progeroid features. | Van Esch H | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16278265 |
Analysis of genetic variations of lamin A/C gene (LMNA) by denaturing high-performance liquid chromatography. | Taylor MR | Journal of biomolecular screening | 2004 | PMID: 15475483 |
Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. | Taylor MR | Journal of the American College of Cardiology | 2003 | PMID: 12628721 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c2d33e92-149f-46d8-95bf-19a2fdde97e3 | - | - | - | - |
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Text-mined citations for rs60890628 ...
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.