rs267607571

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000368300.9(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. 13/22 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 ENST00000368300.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 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

Verdict is Pathogenic. Variant got 19 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, 8 uncertain in ENST00000368300.9
• 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.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ 2.3673 (greater than the threshold 3.09). Trascript score misZ 3.0905 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.964
• 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/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.569G>A	p.Arg190Gln	missense_variant	3/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.569G>A	p.Arg190Gln	missense_variant	3/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.569G>A	p.Arg190Gln	missense_variant	3/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.569G>A	p.Arg190Gln	missense_variant	3/10		NM_005572.4	ENSP00000503633

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

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 17, 2021	PS3, PS4_moderate, PM1, PM2, PM5, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2022	- -

Cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 06, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 23, 2019	This missense variant replaces arginine with glutamine at codon 190 of the intermediate filament rod domain of the lamin A/C protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 two unrelated individuals (PMID: 18795223, 26899768) and three related individuals affected with dilated cardiomyopathy (PMID: 20160190). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same amino acid position (p.Arg190Trp) is thought to be disease-causing (Clinvar variation ID 66908). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2022	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. -

Primary dilated cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 25, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 13, 2020	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. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

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). 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 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Dec 13, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2021

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. -

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;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
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

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;