rs201583907

Variant names:

• chr1-156137191-G-A
• rs201583907
• NM_170707.4:c.1567G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156137191-G-A
• chr1-156137191-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_170707.4(LMNA):​c.1567G>A​(p.Gly523Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000809 in 1,606,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:19 O:1
• Conservation: PhyloP100: 9.92

Genes affected

LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_170707.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the LMNA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 2.3673 (below the threshold of 3.09). Trascript score misZ: 3.0905 (above the threshold of 3.09). GenCC associations: The gene is linked to familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1567G>A	p.Gly523Arg	missense_variant	Exon 9 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1567G>A	p.Gly523Arg	missense_variant	Exon 9 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1567G>A	p.Gly523Arg	missense_variant	Exon 9 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1567G>A	p.Gly523Arg	missense_variant	Exon 9 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000856 AC: 20 AN: 233624 Hom.: 0 AF XY: 0.0000946 AC XY: 12 AN XY: 126878

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000825 AC: 120 AN: 1454642 Hom.: 0 Cov.: 32 AF XY: 0.0000788 AC XY: 57 AN XY: 723212

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:10 Other:1

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Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Aug 05, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 16, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Oct 19, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Feb 05, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 38979608, 24623722, 37425136, 37624850, 19318026, 35026164, 31476771, 36397776, 34720847, 32826072, 29961767, 30919684, 10939567, 37652022) -

Cardiomyopathy Uncertain:2

Jul 08, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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May 10, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Left ventricular noncompaction Pathogenic:1

Apr 19, 2017

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

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not specified Uncertain:1

Feb 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 with dilated cardiomyopathy, limb-girdle muscular dystrophy, dyslipidemia, and EmeryDreifuss muscular dystrophy, without strong evidence of causality (example: Hylind_2019, Millat_2009, Millat_2011, Pugh_2014, Haas_2015, Park_2020, Pena-Pena_2021, Magri_2015, Fichna_2018, Dron_2020, McGurk_2023, Cannie_2023, Boen_2024, Garcia-Pavia_2024). 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). Two studies have shown the variant is unlikely to contribute to disease (Gregory_2023, and Anderson_2021). The following publications have been ascertained in the context of this evaluation (PMID: 38689299, 37639473, 24623722, 32041611, 29970176, 38979608, 37624850, 25163546, 30919684, 26404900, 37652022, 19318026, 21846512, 31383942, 32826072, 24503780,34862408). ClinVar contains an entry for this variant (Variation ID: 48045). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, dyslipidemias, or atrial fibrillation (PMID: 19318026, 24503780, 26404900, 29970176, 32041611, 34495297). ClinVar contains an entry for this variant (Variation ID: 48045). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. 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. -

Lethal tight skin contracture syndrome Uncertain:1

Jun 21, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Primary dilated cardiomyopathy Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dilated cardiomyopathy 1A Uncertain:1

Feb 28, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Uncertain:1

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Cardiovascular phenotype Uncertain:1

Jul 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;.;.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;T;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.;M;M;M;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.;.
Vest4		0.99
MutPred		0.86		Gain of MoRF binding (P = 0.0148);.;Gain of MoRF binding (P = 0.0148);Gain of MoRF binding (P = 0.0148);Gain of MoRF binding (P = 0.0148);.;.;.;.;
MVP		0.99
MPC		1.2
ClinPred		0.91	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201583907; hg19: chr1-156106982;