rs769561386

Positions:

chr1-156138575-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_170707.4(LMNA):c.1786G>A(p.Asp596Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 7.42

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1786G>A	p.Asp596Asn	missense_variant	11/12	ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.1786G>A	p.Asp596Asn	missense_variant	11/12	1	NM_170707.4	ENSP00000357283	P1	P02545-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

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:

0.0000204

AC:

AN:

245632

Hom.:

AF XY:

0.0000299

AC XY:

AN XY:

133786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000363

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1460348

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726468

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

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:

0.0000808

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2021	Reported in one individual with limb girdle muscular dystrophy who presented with DCM and heart failure (Correa and Gmez, 2007); Published functional studies using fibroblast cell lines derived from a patient harboring the D596N variant found that while chromosome 13 was maintained at the nuclear periphery, there was gross mislocalization of this chromosome, suggesting that D596N impacts the nuclear lamina's ability to interact with chromatin (Mewborn et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21818408, 21970986, 10939567, 24481844, 27507988, 27200088, 29907918, 21520333, 21179469, 18035816) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -

Muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 596 of the LMNA protein (p.Asp596Asn). This variant is present in population databases (rs769561386, gnomAD 0.005%). This missense change has been observed in individuals with Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 18035816, 21520333). ClinVar contains an entry for this variant (Variation ID: 435774). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 16, 2023

This missense variant replaces aspartic acid with asparagine at codon 596 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies using fibroblasts derived from heterozygous carrier individuals for this variant have shown this variant causes abnormal localization of chromosome 13 within the nuclei, suggesting impaired interaction with chromatin (PMID: 21179469, 21818408). This variant has been reported in an individual affected with limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 18035816) and in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 21520333). This variant has been identified in 6/277018 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. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

This missense variant replaces aspartic acid with asparagine at codon 596 of the lamin A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 18035816) and in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 21520333). This variant has been identified in 6/277018 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

CardioboostCm

Benign

0.0056

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

.;T;.;.;.;T

Eigen

Benign

-0.030

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.47

T;T;T;T;T;T

MetaSVM

Uncertain

-0.013

MutationAssessor

Benign

1.5

.;L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.1

N;N;N;N;N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.0040

D;D;D;D;D;D

Sift4G

Benign

0.47

T;T;T;T;T;T

Polyphen

0.086

B;B;.;.;.;.

Vest4

0.59

MutPred

0.67

.;Loss of stability (P = 0.0652);Loss of stability (P = 0.0652);.;.;.;

MVP

0.84

MPC

0.33

ClinPred

0.53

GERP RS

5.0

Varity_R

0.17

gMVP

0.73

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

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