rs267607555

chr1-156136009-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_170707.4(LMNA):c.1045C>T(p.Arg349Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,046 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R349L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1 O:2
• Conservation: PhyloP100: 0.897

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 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr1-156136010-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2860240.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 1-156136009-C-T is Pathogenic according to our data. Variant chr1-156136009-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66762.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Likely_pathogenic=2, not_provided=2, Uncertain_significance=1}. Variant chr1-156136009-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1045C>T	p.Arg349Trp	missense_variant	6/12	ENST00000368300.9
LMNA	NM_005572.4	c.1045C>T	p.Arg349Trp	missense_variant	6/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1045C>T	p.Arg349Trp	missense_variant	6/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1045C>T	p.Arg349Trp	missense_variant	6/10		NM_005572.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 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 AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

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

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2013	p.Arg349Trp (CGG>TGG): c.1045 C>T in exon 6 of the LMNA gene (NM_170707.2). The Arg349Trp mutation in the LMNA gene has been reported in one individual with atypical partial lipodystrophy (Mory P et al., 2012). In addition, a mutation affecting this same residue, (Arg349Leu), has been reported in three individuals from one family, all of whom required cardiac transplantation at ages 18, 20, and 36 years (Hermida-Prieto M et al., 2004). Mutations in nearby residues (Glu347Lys, Ala350Pro, Gln353Lys) have been reported in association with DCM and conduction defects, further supporting the functional importance of this residue and this region of the protein. Arg349Trp was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Arg349Trp in the LMNA gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s). -
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	Jul 24, 2020	PS4, PP1_strong, PM2, PM5, PP3 -

Familial partial lipodystrophy, Dunnigan type Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R349W in LMNA (NM_170707.4) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported to segregate in a family affected with partial lipodystrophy and renal disease (Thong et al., 2013) and has been reported in individuals with lipodystrophy with and without renal disease or dilated cardiomyopathy including one individual in whom the variant was de novo (Tintelen et al., 2007; Fountas et al., 2017; van SpaendonckZwarts et al., 2013; Akinci et al., 2017; Mory et al., 2012). The p.R349W variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The gene LMNA contains 112 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 17, 2015	- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 349 of the LMNA protein (p.Arg349Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with lipodystrophy and/or renal disease or dilated cardiomyopathy (PMID: 18035086, 22700598, 23349452, 24080738, 28620495, 28641778). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66762). 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%. This variant disrupts the p.Arg349 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15219508, 25163546, 27532257). 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. -

Monogenic diabetes Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Translational Genomics Laboratory, University of Maryland School of Medicine

Oct 27, 2017

The c.1045C>T variant in codon 349 (exon 6) of the Lamin A/C gene, LMNA, results in the substitution of Arginine to Tryptophan. Mutations in the LMNA gene have been found to cause multiple disorders, collectively known as A-type laminopathies, that have overlapping signs and symptoms (23853504; 20074070; OMIM 150330). A-type laminopathies include familial partial lipodystrophy type 2 (also called familial partial lipodystrophy, Dunnigan type), Limb-Girdle muscular dystrophy type 1B, Emery-Dreifuss muscular dystrophy, Charcot-Marie-Tooth type 2B1 disease, Hutchinson-Gilford progeria, Heart-hand syndrome, Slovenian type, mandibuloacral dysplasia, Malouf syndrome, and familial dilated cardiomyopathy.1-3 To date, no clear genotype-phenotype correlations have been identified (23853504; 20074070). The c.1045C>T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the p.Arg349Trp substitution has been identified in patients with skeletal, cardiac and metabolic phenotypes (23853504; 24080738; 2270059). The c.1045C>T variant has been identified in multiple affected individuals in four generations of a family with familial partial lipodystrophy4, as well as in an 18-year old boy with atypical partial lipodystrophy as a de novo change (2270059). A different amino acid change at this same residue, p.Arg349Leu, was identified in a mother and two daughters with dilated cardiomyopathy (15219508). Additionally, multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, FATHMM, MetaSVM, MetalR, Provean, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PM2, PM6, PP1, PP3 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 02, 2021

- -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 26, 2023

This missense variant replaces arginine with tryptophan at codon 349 in the intermediate filament rod domain of the lamin A/C 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 18035086, 23183350, 23349452, 27813223, 28790152, 31521807) and in individuals affected with unspecified cardiomyopathy (PMID: 28679633, 31383942). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Due to the insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy. However, this variant has also been reported in individuals affected with familial partial lipodystrophy, both with and without cardiac involvement (PMID: 22700598, 24080738, 28620495, 28641778, 31794942, 32413188, 32517491, 32939435, 36397776). This variant segregated with disease in multiple individuals affected with familial partial lipodystrophy, both with and without cardiac involvement, in one extended family (PMID: 24080738). It has also been reported in individuals affected with atypical progeroid syndrome with partial lipodystrophy and cardiac abnormalities (PMID: 35384599). Familial partial lipodystrophy is a rare autosomal dominant condition characterized by an abnormal distribution of fatty tissue in the body and associated with metabolic involvement, such as diabetes, hyperlipidemia, and hepatosteatosis, as well as various cardiovascular complications. We recommend you discuss this finding with your healthcare provider. Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause familial partial lipodystrophy (ClinVar variation ID: 66762). -

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

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as pathogenic and reported on 09/04/2018 by 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.5	M;.;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.
Vest4		0.95
MutPred		0.74		Gain of catalytic residue at M352 (P = 0.0387);Gain of catalytic residue at M352 (P = 0.0387);Gain of catalytic residue at M352 (P = 0.0387);Gain of catalytic residue at M352 (P = 0.0387);Gain of catalytic residue at M352 (P = 0.0387);.;.;.;
MVP		0.93
MPC		2.0
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.74
gMVP		0.97

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: rs267607555; hg19: chr1-156105800; COSMIC: COSV100738834; COSMIC: COSV100738834;