rs61195471

Positions:

• chr1-156134496-G-A

Variant summary

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

The NM_170707.4(LMNA):​c.607G>A​(p.Glu203Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E203G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:3
• 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 region_of_interest Coil 1B (size 137) in uniprot entity LMNA_HUMAN there are 60 pathogenic changes around while only 0 benign (100%) 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 chr1-156134497-A-G is described in Lovd as [Pathogenic].
• 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, 0.982
• PP5: Variant 1-156134496-G-A is Pathogenic according to our data. Variant chr1-156134496-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156134496-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.607G>A	p.Glu203Lys	missense_variant	3/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.607G>A	p.Glu203Lys	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.607G>A	p.Glu203Lys	missense_variant	3/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.607G>A	p.Glu203Lys	missense_variant	3/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2021	PS3, PM1, PM2, PM5, PP1_strong, PP3 -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2021	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; Functional studies suggest that the E203K variant disrupts lamin A localization, resulting in protein aggregation and increased cell death (Zhang et al., 2008; Cowen et al., 2010); Reported in ClinVar (ClinVar Variant ID# 48070; ClinVar); This variant is associated with the following publications: (PMID: 29764566, 10580070, 23427149, 18606848, 23582089, 18585512, 18795223, 22464770, 27374873, 11561226, 30934932, 31514951, 31983221, 32455078, 32719615, 32471220, 20160190, 26199943, 20301717, 24556839, 23475188, 22886719, 21639948, 20079693, 19282183, 10939567) -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 203 of the LMNA protein (p.Glu203Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 11561226, 22464770). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48070). 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: 18606848, 20160190). This variant disrupts the p.Glu203 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 10580070, 18795223), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

LMNA-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2024

The LMNA c.607G>A variant is predicted to result in the amino acid substitution p.Glu203Lys. This variant was reported in the heterozygous state in multiple unrelated individuals with dilated cardiomyopathy and/or conduction system disease (Jakobs et al. 2001. PubMed ID: 11561226; Online Table 1, Gigli et al. 2019. PubMed ID: 31514951; Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221; Sheikh et al. 2020. PubMed ID: 32455078). Functional studies showed that this variant resulted in decreased sumoylation and aberrant subcellular localization (Zhang et al. 2008. PubMed ID: 18606848). This variant has not been reported in a large population database, indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Glu203Gly, p.Glu203Val) have been reported in the heterozygous state in individuals with dilated cardiomyopathy and/or conduction system disease (Fatkin et al. 1999. PubMed ID: 10580070; Perrot et al. 2009. PubMed ID: 18795223). Taken together, the c.607G>A (p.Glu203Lys) variant is interpreted as pathogenic. -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 20, 2018

The p.Glu203Lys variant in LMNA has been reported in 2 individuals with dilated cardiomyopathy, and in one family segregated with DCM in two individuals and con duction system disease in another 6 individuals (Jakobs 2001, LMM data). It was also absent from large population studies. This variant has been reported in Cli nVar (Variation ID: 48070). In vitro functional studies provide some evidence th at the p.Glu203Lys variant may impact protein function (Cowan 2010), while anoth er had inconclusive findings (Zwerger 2013). However, these types of assays may not accurately represent biological function. Finally, another missense variant at this position has been reported to segregate with DCM (p.Glu203Gly; Fatkin 19 99). In summary, although additional studies are required to fully establish its clinical significance, the p.Glu203Lys variant is likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_ Strong, PM2, PS3_Supporting, PS4_Supporting. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

The p.E203K pathogenic mutation (also known as c.607G>A), located in coding exon 3 of the LMNA gene, results from a G to A substitution at nucleotide position 607. The glutamic acid at codon 203 is replaced by lysine, an amino acid with similar properties. This variant has been reported in multiple unrelated individuals with dilated cardiomyopathy (DCM) and/or conduction system disease and has been shown to segregate with disease phenotype in one large family (Jakobs PM et al. J. Card. Fail. 2001;7:249-56; Lakdawala NK et al. J. Card. Fail. 2012;18:296-303). In addition, functional studies have demonstrated deficient LMNA protein function both in cell lines expressing E203K and in fibroblasts from patients heterozygous for this mutation (Zhang YQ et al. J. Cell Biol. 2008;182:35-9; Cowan J et al. Circ Cardiovasc Genet. 2010;3:6-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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. -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Pathogenic and reported on 07-09-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Dilated cardiomyopathy 1A Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;D;.;.;.;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.8	H;.;H;H;H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Benign	0.045	D;D;D;D;D;D;D;T;D
Sift4G	Uncertain	0.046	D;D;D;D;D;D;D;T;D
Polyphen		0.98	D;.;D;D;.;.;D;.;.
Vest4		0.93
MutPred		0.94		Gain of MoRF binding (P = 0.0039);Gain of MoRF binding (P = 0.0039);Gain of MoRF binding (P = 0.0039);Gain of MoRF binding (P = 0.0039);Gain of MoRF binding (P = 0.0039);.;.;.;.;
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.60
gMVP		0.98

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: rs61195471; hg19: chr1-156104287;