rs267607571

Variant names:

• chr1-156134458-G-A
• rs267607571
• NM_170707.4:c.569G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156134458-G-A
• chr1-156134458-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_170707.4(LMNA):​c.569G>A​(p.Arg190Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 9.94

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

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_170707.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156134457-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 66908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 1-156134458-G-A is Pathogenic according to our data. Variant chr1-156134458-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156134458-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.569G>A	p.Arg190Gln	missense_variant	Exon 3 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.569G>A	p.Arg190Gln	missense_variant	Exon 3 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.569G>A	p.Arg190Gln	missense_variant	Exon 3 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.569G>A	p.Arg190Gln	missense_variant	Exon 3 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53402

Gnomad4 NFE exome AF: 0.00000360 AC: 4 AN: 1112000

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000959 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Dec 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in at least one individual with Emery-Dreifuss muscular dystrophy type 2 (EDMD2); this individual also harbored a second variant in the same LMNA allele, previously published in association with EDMD2 (PMID: 15744034, 31744510); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrated COS7 cells expressing GFP-prelamin A fusion constructs including the p.(R190Q) variant showed mild-moderate levels of abnormal nuclear shapes in addition to a significantly greater proportion of nuclei with nuclear envelope-associated aggregates compared to control COS7 cells (PMID: 20160190); This variant is associated with the following publications: (PMID: 24846508, Garcia-Pavia2013[Abstract], 18795223, 28069705, 26899768, 11897440, 28416588, 23701190, 24386194, 29693488, 29764566, 31447099, 31983221, 31383942, 30453078, 31744510, 15744034, 18585512, 36264615, 34862408, 35288587, 36396199, 10939567, 20160190, 37652022) -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 17, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM1, PM2, PM5, PP1, PP3 -

Sep 27, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Pathogenic:3

Feb 16, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 190 in the intermediate filament rod domain of the LMNA protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant causes abnormal localization of lamin A in the nuclear envelope (PMID: 20160190). This variant has been reported in at least nine unrelated individuals affected with dilated cardiomyopathy (PMID: 18585512, 18795223, 20160190, 26899768, 28790152, 29773157, 31983221, 34773379, 35288587). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 20160190). This variant has also been reported in two individuals affected with an unspecified cardiomyopathy (PMID: 31383942) and in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705). In addition, this variant has been reported in one individual affected with Emery-Dreifuss muscular dystrophy who also carried an additional pathogenic variant in the LMNA gene (PMID: 15744034). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg190Trp, is considered to be disease-causing (ClinVar variation ID: 66908), suggesting that arginine at this position is important for LMNA protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aug 15, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LMNA c.569G>A (p.Arg190Gln) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251370 control chromosomes. c.569G>A has been reported in the literature in multiple individuals affected with familial dilated cardiomyopathy/Lamin A/C cardiomyopathies (example, Parks_2008, Perrot_2009, Cowan_2010, Cuenca_2016, Te Riele_2017, Park_2020, Gerbino_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated membrane bound GFP-lamin A aggregates and nuclear shape abnormalities supporting a pathogenic outcome (Cowan_2010). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 06, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Pathogenic:2

Feb 13, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg190Gln variant in LMNA has been reported in the heterozygous state in 3 individuals with DCM, and in 2 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC; Cuenta 2016, Parks 2008, Perrot 2009, Poloni 2019, Te Riele 2017). It has also been identified in 1 individual with Emery-Dreifuss muscular dystrophy (EDMD) who harbored a second LMNA variant in cis that has been classified as pathogenic for EDMD (Cenni 2005). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 66910) and was absent from large population studies. In vitro functional studies support an impact on protein function (Cowan 2010) and computational prediction tools and conservation analysis suggest that the p.Arg190Gln variant may impact the protein. Another variant at the same position, p.Arg190Trp has been reported in several individuals with DCM and is classified as pathogenic by several clinical laboratories in ClinVar (Variation ID 66908, Arbustini 2002, Sylvius 2005, Vaikhanskaya 2014). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PM2, PM5, PP3, PS3_Supporting, PS4_Supporting. -

Apr 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 190 in the intermediate filament rod domain of the LMNA protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant causes abnormal localization of lamin A in the nuclear envelope (PMID: 20160190). This variant has been reported in at least nine unrelated individuals affected with dilated cardiomyopathy (PMID: 18585512, 18795223, 20160190, 26899768, 28790152, 29773157, 31983221, 34773379, 35288587). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 20160190). This variant has also been reported in two individuals affected with an unspecified cardiomyopathy (PMID: 31383942) and in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705). In addition, this variant has been reported in one individual affected with Emery-Dreifuss muscular dystrophy who also carried an additional pathogenic variant in the LMNA gene (PMID: 15744034). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg190Trp, is considered to be disease-causing (ClinVar variation ID: 66908), suggesting that arginine at this position is important for LMNA protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:2

Jun 09, 2021

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R190Q pathogenic mutation (also known as c.569G>A), located in coding exon 3 of the LMNA gene, results from a G to A substitution at nucleotide position 569. The arginine at codon 190 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with dilated cardiomyopathy (DCM) (Parks SB et al. Am. Heart J., 2008 Jul;156:161-9; Perrot A et al. Basic Res. Cardiol., 2009 Jan;104:90-9; Park J et al. Genet Med, 2020 01;22:102-111; Mazzarotto F et al. Circulation, 2020 02;141:387-398). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 190 of the LMNA protein (p.Arg190Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant LMNA-related conditions (PMID: 18795223, 20160190, 26899768). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66910). 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 have shown that this missense change affects LMNA function (PMID: 20160190). This variant disrupts the p.Arg190 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11897440, 23701190, 24386194, 28416588). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1A Pathogenic:1

Dec 13, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;.;D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.3	M;.;M;M;M;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.;.
Vest4		0.91
MutPred		0.86		Loss of MoRF binding (P = 0.0485);Loss of MoRF binding (P = 0.0485);Loss of MoRF binding (P = 0.0485);Loss of MoRF binding (P = 0.0485);Loss of MoRF binding (P = 0.0485);.;.;.;.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.87
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs267607571; hg19: chr1-156104249; COSMIC: COSV61542038; COSMIC: COSV61542038;