VCV000048045.38 - ClinVar

NM_170707.4(LMNA):c.1567G>A (p.Gly523Arg)

Germline

Classification

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.

(20)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_170707.4(LMNA):c.1567G>A (p.Gly523Arg)

Variation ID: 48045 Accession: VCV000048045.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 156137191 (GRCh38) [ NCBI UCSC ] 1: 156106982 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Sep 16, 2024	Feb 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_170707.4:c.1567G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_733821.1:p.Gly523Arg	missense
NM_005572.4:c.1567G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005563.1:p.Gly523Arg	missense
NM_001257374.3:c.1231G>A	NP_001244303.1:p.Gly411Arg	missense
NM_001282624.2:c.1324G>A	NP_001269553.1:p.Gly442Arg	missense
NM_001282625.2:c.1567G>A	NP_001269554.1:p.Gly523Arg	missense
NM_001282626.2:c.1567G>A	NP_001269555.1:p.Gly523Arg	missense
NM_170708.4:c.1567G>A	NP_733822.1:p.Gly523Arg	missense
NC_000001.11:g.156137191G>A
NC_000001.10:g.156106982G>A
NG_008692.2:g.59619G>A
LRG_254:g.59619G>A
LRG_254t2:c.1567G>A
	P02545:p.Gly523Arg

... more HGVS ... less HGVS

Protein change

G523R, G411R, G442R

Other names

Canonical SPDI

NC_000001.11:156137190:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00009

Exome Aggregation Consortium (ExAC) 0.00011

Links

ClinGen: CA017464 UniProtKB: P02545#VAR_067258 dbSNP: rs201583907 VarSome

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
Gene	OMIM	HI score Help 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.
LMNA		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1847	2129

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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.
not specified	Uncertain significance (1)	criteria provided, multiple submitters, no conflicts	Feb 20, 2023	RCV000041324.10
not provided	Uncertain significance (11)	criteria provided, multiple submitters, no conflicts	Feb 24, 2024	RCV000057323.21
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jul 20, 2023	RCV000245950.5
Charcot-Marie-Tooth disease type 2	Uncertain significance (1)	criteria provided, single submitter	Nov 1, 2022	RCV000474372.9
Left ventricular noncompaction	no classifications from unflagged records (1)	no classifications from unflagged records	Oct 16, 2023	RCV000678714.2
Lethal tight skin contracture syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 21, 2019	RCV001330499.1
Cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	May 10, 2023	RCV001181346.5
Dilated cardiomyopathy 1A	Uncertain significance (1)	criteria provided, single submitter	Feb 28, 2020	RCV001250579.1
Primary dilated cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Feb 5, 2024	RCV003996456.2

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 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.
Uncertain significance (Nov 01, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000548848.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (7) PubMed: 28492532‚ 19318026‚ 24503780‚ 26404900‚ 29970176‚ 32041611‚ 24623722 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 523 of the LMNA protein (p.Gly523Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 523 of the LMNA protein (p.Gly523Arg). This variant is present in population databases (rs201583907, gnomAD 0.01%). This missense change has been observed in individual(s) with limb girdle muscular dystrophy, dilated cardiomyopathy, or dyslipidemias (PMID: 19318026, 24503780, 26404900, 29970176, 32041611). ClinVar contains an entry for this variant (Variation ID: 48045). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 24623722). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jul 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004240717.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Uncertain Significance (Aug 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000065017.7 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (4) PubMed: 19318026‚ 24503780‚ 26404900‚ 29970176 Comment: The p.Gly523Arg variant in LMNA has been reported in 5 individual with dilated cardiomyopathy (DCM; Millat 2009 PMID: 19318026, Fichna 2018 PMID: 29970176, LMM data), … (more) The p.Gly523Arg variant in LMNA has been reported in 5 individual with dilated cardiomyopathy (DCM; Millat 2009 PMID: 19318026, Fichna 2018 PMID: 29970176, LMM data), 1 individual with limb-girdle muscular dystrophy (Magri 2015 PMID: 26404900), 1 individual with LVNC, conduction system disease and muscle weakness (LMM data), and in 2 siblings presenting with features of COL6A2 related myopathy as well as Emery-Dreifuss muscular dystrophy (Chapon 2008, conference abstract only). In the family described by Chapon et al, the myopathy present in both sibs was believed to be due recessively inherited COL6A2 variants. The LMNA variant was present in one of the sibs as well as the father, who was clinically normal but showed dystrophic changes as well as mild deficit of collagen 6 fibers. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 48045 ) and has been identified in 0.01% (8/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3. (less)
Uncertain significance (Jul 20, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000320458.8 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (16) PubMed: 19318026‚ 21846512‚ 24503780‚ 24623722‚ 26404900‚ 28663758‚ 29961767‚ 29970176‚ 30919684‚ 31383942‚ 31476771‚ 31744510‚ 34495297‚ 34720847‚ 34862408‚ 36397776 Comment: The p.G523R variant (also known as c.1567G>A), located in coding exon 9 of the LMNA gene, results from a G to A substitution at nucleotide … (more) The p.G523R variant (also known as c.1567G>A), located in coding exon 9 of the LMNA gene, results from a G to A substitution at nucleotide position 1567. The glycine at codon 523 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in individuals with dilated cardiomyopathy (DCM) (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Millat G et al. Clin. Biochem., 2009 Jun;42:892-8; Millat G et al. Eur J Med Genet Aug;54:e570-5; Hylind RJ et al. Circ Genom Precis Med. 2019 Mar;12(3):e002463). This variant has also been detected in individuals with limb girdle muscular dystrophy (LGMD); however, in some cases, other variants in myopathy-related genes were also detected (Magri F et al. BMC Neurol, 2015 Sep;15:172; Fichna JP et al. Hum. Genomics, 2018 07;12:34). This variant has also been detected in two individual from familial partial lipodystrophy cohort; however details were limited (Vasandani C et al. J Endocr Soc. 2022 Oct;6(12):bvac155). This variant was also reported in 35 individuals from an electronic medical record review exome cohort, including one DCM case and two individuals with chronic kidney disease (Park J et al. Genet Med, 2020 01;22:102-111). This amino acid position is highly 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)
Uncertain significance (Jun 21, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522189.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Feb 24, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000234703.7 First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024	Comment: Observed to segregate with DCM, conduction disease, and/or subtle right ventricular abnormalities in individuals from one family, but was also observed in unaffected individuals in … (more) Observed to segregate with DCM, conduction disease, and/or subtle right ventricular abnormalities in individuals from one family, but was also observed in unaffected individuals in this family (PMID: 30919684); Published functional studies demonstrate altered ability of LMNA protein to interact with 5% of its protein targets; however, it is unclear how these studies may translate to a pathogenic role in vivo (PMID: 24623722); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24375749, 24503780, 24846508, 21846512, 26404900, 25163546, 28663758, 28679633, 27576561, 26633542, 29970176, 31744510, 32193531, 31383942, 32041611, 34495297, 34862408, 24623722, 37425136, 37624850, 19318026, 35026164, 31476771, 36397776, 34720847, 32826072, 29961767, 30919684, 10939567) (less)
Uncertain significance (Aug 16, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000336479.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA Number of individuals with the variant: 3 Sex: mixed
Uncertain significance (Feb 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1A Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001425445.1 First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020	Publications: PubMed (6) PubMed: 19318026‚ 21846512‚ 24375749‚ 24623722‚ 28663758‚ 29970176
Uncertain significance (Feb 20, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003845078.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (8) PubMed: 21846512‚ 24503780‚ 19318026‚ 25163546‚ 31383942‚ 24623722‚ 30919684‚ 32826072 Comment: Variant summary: LMNA c.1567G>A (p.Gly523Arg) results in a non-conservative amino acid change located in the Lamin tail domain (IPR001322) of the encoded protein sequence. Five … (more) Variant summary: LMNA c.1567G>A (p.Gly523Arg) results in a non-conservative amino acid change located in the Lamin tail domain (IPR001322) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.6e-05 in 233624 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LMNA causing Cardiomyopathy (8.6e-05 vs 0.00025), allowing no conclusion about variant significance. c.1567G>A has been reported in the literature in individuals affected with limb girdle muscular dystrophy, dilated cardiomyopathy, or other dyslipidemias (Millat_2011, Pugh_2014, Park_2020, etc). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Dittmer_2014). Nine ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=8) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Oct 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003816997.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (May 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001346472.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (14) PubMed: 19318026‚ 21846512‚ 24503780‚ 24623722‚ 26404900‚ 28663758‚ 29961767‚ 30919684‚ 31383942‚ 31744510‚ 32193531‚ 32826072‚ 34720847‚ 35026164 Comment: This missense variant replaces glycine with arginine at codon 523 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact … (more) This missense variant replaces glycine with arginine at codon 523 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study using a yeast two hybrid system has shown that this variant may lead to ~5% lost protein interactions (PMID: 24623722), but functional and clinical significance of this observation is not known. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19318026, 21846512, 24503780, 29961767, 30919684, 31383942), in an individual affected with hypertrophic cardiomyopathy (PMID: 35026164), and in individuals affected with limb girdle muscular dystrophy (PMID: 26404900, 34720847). This variant has been reported in four members of one family (PMID: 30919684); one carrier was affected with subtle right ventricular abnormalities, and the carrier's parent was affected with dilated cardiomyopathy and conduction disease. This variant has also been reported in individuals affected with laminopathy (PMID: 28663758, 31744510, 32193531, 32826072), in individuals affected with chronic kidney disease (PMID: 31383942), and in multiple apparently healthy individuals in a large biobank (PMID: 31383942). This variant has been identified in 22/264998 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)
Uncertain Significance (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary dilated cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004817446.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (14) PubMed: 19318026‚ 21846512‚ 24503780‚ 24623722‚ 26404900‚ 28663758‚ 29961767‚ 30919684‚ 31383942‚ 31744510‚ 32193531‚ 32826072‚ 34720847‚ 35026164 Comment: This missense variant replaces glycine with arginine at codon 523 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact … (more) This missense variant replaces glycine with arginine at codon 523 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study using a yeast two hybrid system has shown that this variant may lead to ~5% lost protein interactions (PMID: 24623722), but functional and clinical significance of this observation is not known. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19318026, 21846512, 24503780, 29961767, 30919684, 31383942), in an individual affected with hypertrophic cardiomyopathy (PMID: 35026164), and in individuals affected with limb girdle muscular dystrophy (PMID: 26404900, 34720847). This variant has been reported in four members of one family (PMID: 30919684); one carrier was affected with subtle right ventricular abnormalities, and the carrier's parent was affected with dilated cardiomyopathy and conduction disease. This variant has also been reported in individuals affected with laminopathy (PMID: 28663758, 31744510, 32193531, 32826072), in individuals affected with chronic kidney disease (PMID: 31383942), and in multiple apparently healthy individuals in a large biobank (PMID: 31383942). This variant has been identified in 22/264998 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) Number of individuals with the variant: 14
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918068.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807449.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743354.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931676.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001954184.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001963796.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Epithelial Biology; Institute of Medical Biology, Singapore Accession: SCV000088436.1 First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013
Likely pathogenic (Apr 19, 2017)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Left ventricular noncompaction Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000804881.1 First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018
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Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 523 of the LMNA protein (p.Gly523Arg). This variant is present in population databases (rs201583907, gnomAD 0.01%). This missense change has been observed in individual(s) with limb girdle muscular dystrophy, dilated cardiomyopathy, or dyslipidemias (PMID: 19318026, 24503780, 26404900, 29970176, 32041611). ClinVar contains an entry for this variant (Variation ID: 48045). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 24623722). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.Gly523Arg variant in LMNA has been reported in 5 individual with dilated cardiomyopathy (DCM; Millat 2009 PMID: 19318026, Fichna 2018 PMID: 29970176, LMM data), 1 individual with limb-girdle muscular dystrophy (Magri 2015 PMID: 26404900), 1 individual with LVNC, conduction system disease and muscle weakness (LMM data), and in 2 siblings presenting with features of COL6A2 related myopathy as well as Emery-Dreifuss muscular dystrophy (Chapon 2008, conference abstract only). In the family described by Chapon et al, the myopathy present in both sibs was believed to be due recessively inherited COL6A2 variants. The LMNA variant was present in one of the sibs as well as the father, who was clinically normal but showed dystrophic changes as well as mild deficit of collagen 6 fibers. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 48045 ) and has been identified in 0.01% (8/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3.

Comment:

The p.G523R variant (also known as c.1567G>A), located in coding exon 9 of the LMNA gene, results from a G to A substitution at nucleotide position 1567. The glycine at codon 523 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in individuals with dilated cardiomyopathy (DCM) (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Millat G et al. Clin. Biochem., 2009 Jun;42:892-8; Millat G et al. Eur J Med Genet Aug;54:e570-5; Hylind RJ et al. Circ Genom Precis Med. 2019 Mar;12(3):e002463). This variant has also been detected in individuals with limb girdle muscular dystrophy (LGMD); however, in some cases, other variants in myopathy-related genes were also detected (Magri F et al. BMC Neurol, 2015 Sep;15:172; Fichna JP et al. Hum. Genomics, 2018 07;12:34). This variant has also been detected in two individual from familial partial lipodystrophy cohort; however details were limited (Vasandani C et al. J Endocr Soc. 2022 Oct;6(12):bvac155). This variant was also reported in 35 individuals from an electronic medical record review exome cohort, including one DCM case and two individuals with chronic kidney disease (Park J et al. Genet Med, 2020 01;22:102-111). This amino acid position is highly 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.

Comment:

Observed to segregate with DCM, conduction disease, and/or subtle right ventricular abnormalities in individuals from one family, but was also observed in unaffected individuals in this family (PMID: 30919684); Published functional studies demonstrate altered ability of LMNA protein to interact with 5% of its protein targets; however, it is unclear how these studies may translate to a pathogenic role in vivo (PMID: 24623722); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24375749, 24503780, 24846508, 21846512, 26404900, 25163546, 28663758, 28679633, 27576561, 26633542, 29970176, 31744510, 32193531, 31383942, 32041611, 34495297, 34862408, 24623722, 37425136, 37624850, 19318026, 35026164, 31476771, 36397776, 34720847, 32826072, 29961767, 30919684, 10939567)

Comment:

Variant summary: LMNA c.1567G>A (p.Gly523Arg) results in a non-conservative amino acid change located in the Lamin tail domain (IPR001322) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.6e-05 in 233624 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LMNA causing Cardiomyopathy (8.6e-05 vs 0.00025), allowing no conclusion about variant significance. c.1567G>A has been reported in the literature in individuals affected with limb girdle muscular dystrophy, dilated cardiomyopathy, or other dyslipidemias (Millat_2011, Pugh_2014, Park_2020, etc). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Dittmer_2014). Nine ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=8) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This missense variant replaces glycine with arginine at codon 523 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study using a yeast two hybrid system has shown that this variant may lead to ~5% lost protein interactions (PMID: 24623722), but functional and clinical significance of this observation is not known. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19318026, 21846512, 24503780, 29961767, 30919684, 31383942), in an individual affected with hypertrophic cardiomyopathy (PMID: 35026164), and in individuals affected with limb girdle muscular dystrophy (PMID: 26404900, 34720847). This variant has been reported in four members of one family (PMID: 30919684); one carrier was affected with subtle right ventricular abnormalities, and the carrier's parent was affected with dilated cardiomyopathy and conduction disease. This variant has also been reported in individuals affected with laminopathy (PMID: 28663758, 31744510, 32193531, 32826072), in individuals affected with chronic kidney disease (PMID: 31383942), and in multiple apparently healthy individuals in a large biobank (PMID: 31383942). This variant has been identified in 22/264998 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.

Comment:

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants.	Vasandani C	Journal of the Endocrine Society	2022	PMID: 36397776
The genetic architecture of pediatric cardiomyopathy.	Ware SM	American journal of human genetics	2022	PMID: 35026164
Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance.	Anderson CL	NPJ genomic medicine	2021	PMID: 34862408
Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb-Girdle Muscular Dystrophy Patients.	Macias A	Frontiers in neuroscience	2021	PMID: 34720847
Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.	Yoneda ZT	JAMA cardiology	2021	PMID: 34495297
Clinical utility of genetic testing in patients with dilated cardiomyopathy.	Peña-Peña ML	Medicina clinica	2021	PMID: 32826072
Diagnostic Value of Anthropometric Measurements for Familial Partial Lipodystrophy, Dunnigan Variety.	Vasandani C	The Journal of clinical endocrinology and metabolism	2020	PMID: 32193531
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.	Dron JS	BMC medical genomics	2020	PMID: 32041611
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
Differences in cardiac phenotype and natural history of laminopathies with and without neuromuscular onset.	Ditaranto R	Orphanet journal of rare diseases	2019	PMID: 31744510
Cardiac and Neuromuscular Features of Patients With LMNA-Related Cardiomyopathy.	Peretto G	Annals of internal medicine	2019	PMID: 31476771
Phenotypic Characterization of Individuals With Variants in Cardiovascular Genes in the Absence of a Primary Cardiovascular Indication for Testing.	Hylind RJ	Circulation. Genomic and precision medicine	2019	PMID: 30919684
Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy.	Minoche AE	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29961767
Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients.	Fichna JP	Human genomics	2018	PMID: 29970176
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
ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases.	Magri F	BMC neurology	2015	PMID: 26404900
Atlas of the clinical genetics of human dilated cardiomyopathy.	Haas J	European heart journal	2015	PMID: 25163546
Systematic identification of pathological lamin A interactors.	Dittmer TA	Molecular biology of the cell	2014	PMID: 24623722
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
Mapping disease-related missense mutations in the immunoglobulin-like fold domain of lamin A/C reveals novel genotype-phenotype associations for laminopathies.	Scharner J	Proteins	2014	PMID: 24375749
Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy.	Millat G	European journal of medical genetics	2011	PMID: 21846512
Validation of high-resolution DNA melting analysis for mutation scanning of the LMNA gene.	Millat G	Clinical biochemistry	2009	PMID: 19318026
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA	-	-	-	-
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Text-mined citations for rs201583907 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_170707.4(LMNA):c.1567G>A (p.Gly523Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201583907 ...