rs58672172

Positions:

chr1-156136251-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate

The NM_170707.4(LMNA):c.1195C>T(p.Arg399Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,876 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. R399H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7O:1

Conservation

PhyloP100: 0.179

Variant links:

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 links:

LMNA (HGNC:):

LMNA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-156136252-G-A 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, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1195C>T	p.Arg399Cys	missense_variant	7/12	ENST00000368300.9	NP_733821.1	P02545-1A0A384MQX1
LMNA	NM_005572.4 linkuse as main transcript	c.1195C>T	p.Arg399Cys	missense_variant	7/10	ENST00000677389.1	NP_005563.1	P02545-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.1195C>T	p.Arg399Cys	missense_variant	7/12	1	NM_170707.4	ENSP00000357283.4		P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.1195C>T	p.Arg399Cys	missense_variant	7/10		NM_005572.4	ENSP00000503633.1		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248876

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459646

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726180

show subpopulations

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:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 29, 2024	This missense variant replaces arginine with cysteine at codon 399 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not change nuclear morphology or lamin A localization (PMID: 20160190). Another study has shown that this variant causes a moderate defect in the lamin A assembly, weakens the interaction between lamin A and NUP155, a key component of nuclear pore complexes, and reduces cardiac sodium channel density (PMID: 30488537). However, clinical relevance of these observations is not known. This variant has been reported in an individual affected with an early-onset dilated cardiomyopathy and in his unaffected mother (PMID: 30012837). This proband carried a pathogenic truncation variant in the TTN gene, which was inherited from his affected father. This variant has also been reported in an individual affected with familial partial lipodystrophy (PMID: 17250669) and in an individual affected with atrial fibrillation (PMID: 30488537). This variant has been identified in 3/248876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

not provided

Uncertain:1Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27841971, 28663758, 18585512, 20160190, 17250669, 30012837, 30488537) -

Charcot-Marie-Tooth disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Familial partial lipodystrophy, Dunnigan type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 15, 2023

This missense variant replaces arginine with cysteine at codon 399 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not change nuclear morphology or lamin A localization (PMID: 20160190). Another study has shown that this variant causes a moderate defect in lamin A assembly, weakening the interaction between lamin A and NUP155, a key component of nuclear pore complexes, and reducing cardiac sodium channel density (PMID: 30488537). However, clinical relevance of these observations is not known. This variant has been reported in an individual affected with early-onset dilated cardiomyopathy and in his unaffected mother (PMID: 30012837). This proband also carried a pathogenic truncation variant in the TTN gene, which was inherited from his affected father. This variant has also been reported in an individual affected with familial partial lipodystrophy (PMID: 17250669) and in an individual affected with atrial fibrillation (PMID: 30488537). This variant has been identified in 3/248876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Charcot-Marie-Tooth disease type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2023

ClinVar contains an entry for this variant (Variation ID: 14519). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects LMNA function (PMID: 30488537). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LMNA protein function. This missense change has been observed in individual(s) with lipodystrophy and dilated cardiomyopathy (PMID: 17250699, 20160190). This variant is present in population databases (rs58672172, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 399 of the LMNA protein (p.Arg399Cys). -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 20, 2024

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2021

The p.R399C variant (also known as c.1195C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1195. The arginine at codon 399 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was originally reported in a patient with familial partial lipodystrophy (Lanktree M et al. Clin Genet. 2007;71(2):183-6). The p.R399C variant was also detected in a proband with severe dilated cardiomyopathy but not in his affected father; however, after subsequent analysis, a TTN A-band truncation was also reported in the proband and the affected father (Parks SB et al. Am Heart J. 2008;156(1):161-9; Cowan J et al. Circ Cardiovasc Genet. 2010;3(1):6-14; Cowan JR et al. Circ Genom Precis Med, 2018 07;11:e002038). In vitro studies using transiently expressed fusion constructs showed nuclear morphology and lamin A localization patterns of p.R399C were comparable with wild-type (Cowan et al 2010); additional functional studies suggested some interference with protein interactions involving NUP155; however, clinical impact was not determined (Han M et al. Hum. Mutat., 2019 03;40:310-325). Another alteration at the same codon, p.R399H (c.1196G>A), was reported in a patient with metabolic laminopathy (Decaudain A et al. J Clin Endocrinol Metab. 2007;92(12):4835-44). This amino acid position is not well conserved in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

CardioboostCm

Benign

0.0022

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

.;.;.;D;.;.;.;.;T

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.099

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.031

MutationAssessor

Benign

0.90

L;.;L;L;L;.;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.060

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.089

T;T;T;T;T;D;T;T;D

Sift4G

Benign

0.084

T;T;T;T;T;T;T;T;T

Polyphen

0.97

D;.;D;D;.;.;D;.;.

Vest4

0.54

MutPred

0.86

Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);.;.;.;.;

MVP

0.98

MPC

0.49

ClinPred

0.21

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.12

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over