chr1-156135967-C-T

Position:

• chr1-156135967-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_170707.4(LMNA):​c.1003C>T​(p.Arg335Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R335P) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 2.01

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]

LMNA (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr1-156135968-GG-CC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 451712.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.
• 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, 0.927
• PP5: Variant 1-156135967-C-T is Pathogenic according to our data. Variant chr1-156135967-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156135967-C-T is described in Lovd as [Pathogenic]. Variant chr1-156135967-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1003C>T	p.Arg335Trp	missense_variant	6/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1003C>T	p.Arg335Trp	missense_variant	6/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1003C>T	p.Arg335Trp	missense_variant	6/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1003C>T	p.Arg335Trp	missense_variant	6/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 25, 2020	PS4, PP1_strong, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2024	Not observed in large population cohorts (gnomAD); 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: 34862408, 22266370, 22464770, 22224630, 24503780, 20474083, 26743238, 23811080, 24846508, 27532257, 30165862, 30871747, 31303467, 29709087, 30847666, 31829210, 30528549, 30078822, 34808346, 27723096, 10939567) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Primary dilated cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 24, 2024	This missense variant replaces arginine with tryptophan at codon 335 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. An in vitro functional study has shown that this variant causes nuclear abnormalities and early cellular senescence (PMID: 34808346). Another functional study using a transgenic zebrafish model has shown that this variant causes reduced heart rate, sarcomere disorders and mitochondrial cristae impairment (PMID: 34808346). This variant has been reported in over 10 unrelated individuals affected with dilated cardiomyopathy (PMID: 22224630, 22464770, 24503780, 26743238, 29237675, 27723096, 30165862, 30739589, 30847666, 30871747, 31303467, 32413188, 33887581). It has been shown that this variant segregates with disease in multiple affected individuals across three families (PMID: 22224630, 29237675, 34808346). In one of these families, multiple individuals were also affected with heart-hand syndrome, including brachydactyly, limb abnormalities and cardiac features (PMID: 34808346). This variant has been reported as a de novo occurrence in one affected individual with no family history of dilated cardiomyopathy (PMID: 31303467). This variant has been reported in one individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the MYBPC3 gene (PMID: 29709087). This variant has also been reported in three individuals affected with related laminopathy phenotypes (PMID: 23183350, 23853504, 30528549). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 09, 2019

- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 25, 2022

- -

LMNA-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2023

The LMNA c.1003C>T variant is predicted to result in the amino acid substitution p.Arg335Trp. This variant has been reported in many unrelated individuals with dilated cardiomyopathy (Lakdawala et al 2012. PubMed ID: 22464770; Table S1B in Walsh R et al 2016. PubMed ID: 27532257; Sousa A et al 2019. PubMed ID: 30871747; Martins E et al 2019. PubMed ID: 31303467; Zhang Y et al 2021. PubMed ID: 34808346). The c.1003C>T variant was also reported in a family with heart hand syndrome IV, but an additional intronic variant (c.1609-12T>G) was also detected (Zaragoza MV et al 2016. PubMed ID: 27723096). In vivo experimental studies suggest this variant impacts protein function (Zhang Y et al 2021. PubMed ID: 34808346). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Dilated cardiomyopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 24, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3,PP4. -

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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2022

- -

Heart-hand syndrome, Slovenian type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 11, 2022

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 335 of the LMNA protein (p.Arg335Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 22224630, 24503780, 27532257, 27723096). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36473). 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. For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy;C5392094:Laminopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 06, 2018

The p.Arg335Trp variant in LMNA (ClinVar ID: 36473) was absent from large popula tion studies and has been reported in 9 individuals with a range of phenotypes, all consistent with a laminopathy (1 individual with Emery-Dreifuss muscular dys trophy (EDMD), 1 individual with acro-osteolysis, atrial fibrillation, hypertrig lyceridemia and autoimmune thyroiditis, 1 individual with hand-heart syndrome IV (HHS-IV), and 5 individuals with DCM with or without arrhythmia) (Drouin 2004, Zafeiriou 2005, Lakdawala 2012, Stallmeyer 2012, Walsh 2016, Nishiuchi 2017, Zar agoza 2017). The variant segregated with disease in 7 individuals (HHS-IV: 3 mem bers of 1 family [Zaragoza 2017], DCM+arrhythmia: 3 members of 3 families [Stall meyer 2012, Nishiuchi 2017, LMM data], EDMD: 1 member of 1 family [Zafeiriou 200 5. In vitro protein modeling provides some evidence that the p.Arg335Trp variant may impact protein function (Bollati 2012). In summary, this variant meets crit eria to be classified as pathogenic for laminopathy in an autosomal dominant man ner. ACMG/AMP Criteria applied: PP1_Strong; PM2; PS4_Moderate; PP3; PS3_Supporti ng. -

Primary familial dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 11, 2023

Variant summary: LMNA c.1003C>T (p.Arg335Trp) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250386 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1003C>T has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy and Heart-Hand syndrome (e.g., Lakdawala_2012, Pugh_2014, Nishiuchi_2017, Zaragoza_2017, Zhang_2022), and the variant has been shown to segregate with Heart-Hand syndrome in at least two families (e.g., Zaragoza_2017, Zhang_2022). 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 found the variant results in abnormal nuclear morphology and contraction as well as defective DNA repair in atrial cardiomyocytes (Zhang_2022). Additionally, when the variant was introduced into a zebrafish model, electrical and structural phenotypes were recapitulated (Zhang_2022). The following publications have been ascertained in the context of this evaluation (PMID: 22464770, 29237675, 24503780, 27723096, 34808346). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Left ventricular noncompaction Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2021

The p.R335W pathogenic mutation (also known as c.1003C>T), located in coding exon 6 of the LMNA gene, results from a C to T substitution at nucleotide position 1003. The arginine at codon 335 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the Coil2 domain. This variant has been reported in multiple individuals with dilated cardiomyopathy (DCM), including one DCM case whose unaffected parents reportedly tested negative for this variant (Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Stallmeyer B et al. Genet Test Mol Biomarkers, 2012 Jun;16:543-9; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Martins E et al. Rev Port Cardiol, 2019 06;38:441-447). This variant has also been reported in individuals with other laminopathies, including one family demonstrating co-segregation in family members with Heart-Hand syndrome type IV, whose symptoms included DCM and brachydactyly (Zaragoza MV et al. Clin Genet, 2017 03;91:499-500; Lambert JC et al. Joint Bone Spine, 2019 07;86:525-527). This variant was not reported in population-based 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	0.59
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.8	H;.;H;H;H;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.
Vest4		0.94
MutPred		0.59		Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);.;.;.;
MVP		0.96
MPC		2.1
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.88
gMVP		0.95

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: rs386134243; hg19: chr1-156105758;