rs28933093

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_170707.4(LMNA):c.481G>A(p.Glu161Lys) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E161E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:2

Conservation

PhyloP100: 10.0

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 Pathogenic. Variant got 17 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, 10 uncertain in NM_170707.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the LMNA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 2.3673 (below the threshold of 3.09). Trascript score misZ: 3.0905 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.978

PP5

Variant 1-156130741-G-A is Pathogenic according to our data. Variant chr1-156130741-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156130741-G-A is described in Lovd as [Pathogenic]. Variant chr1-156130741-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4 link	c.481G>A	p.Glu161Lys	missense_variant	Exon 2 of 12	ENST00000368300.9	NP_733821.1	P02545-1A0A384MQX1
LMNA	NM_005572.4 link	c.481G>A	p.Glu161Lys	missense_variant	Exon 2 of 10	ENST00000677389.1	NP_005563.1	P02545-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 link	c.481G>A	p.Glu161Lys	missense_variant	Exon 2 of 12	1	NM_170707.4	ENSP00000357283.4		P02545-1
LMNA	ENST00000677389.1 link	c.481G>A	p.Glu161Lys	missense_variant	Exon 2 of 10		NM_005572.4	ENSP00000503633.1		P02545-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721142

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00153

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with dilated cardiomyopathy and segregates with disease in multiple individuals from several families (PMID: 12920062, 17334235, 18795223, 24503780, 21846512); Identified in a family with two reported cardiac deaths; seven living family members were heterozygous for this variant, two of whom had DCM with atrial fibrillation and congestive heart failure necessitating heart transplantation, three others had only atrial fibrillation, and two younger individuals were asymptomatic (PMID: 12920062); Not observed at significant frequency in large population cohorts (gnomAD); Functional studies of p.(E161K) in mutant heart and fibroblasts showed that this variant is likely to disrupt normal gene expression due to alteration in the nuclear positioning of chromosomes (PMID: 21179469, 21818408); Additional functional studies in vitro have shown that p.(E161K) results in alteration of protein secondary and tertiary structure with improper oligomerization suggesting that this variant alters mechanotransduction in cardiomyocytes (PMID: 23701190, 24386194); 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: 34768595, 30178466, 30287275, 34862408, 18926329, 24503780, 21818408, 23701190, 26199943, 17334235, 18795223, 21846512, 27532257, 27301336, 28679633, 29432544, 28844980, 31402444, 31737537, 31383942, 32021920, 31744510, 31514951, 30420677, 32880476, 24386194, 36548481, 10939567, 36396199, 21179469, 12920062, 37652022, 35887646, 37728764) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1A

Pathogenic:3Other:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2021

Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as pathogenic and reported on 05/23/2012 by GTR ID 26957. 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. -

Aug 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary dilated cardiomyopathy

Pathogenic:2

Apr 10, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 161 in the intermediate filament rod domain of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in mouse embryonic stem cells have shown that this variant causes increased nuclear blebbing and decreased nuclear lamin organization; additional functional studies have shown that this variant causes changes in the secondary and tertiary structure of the LMNA protein as well as abnormal gene expression profiles (PMID: 21179469, 23701190, 32083564, 35887646). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 12920062, 17334235, 18795223, 18926329, 19318026, 21179469, 27532257, 34768595, 35887646, 35887646). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 18926329, 35887646). 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. -

Jun 26, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy

Pathogenic:1

Apr 30, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 161 of the LMNA protein (p.Glu161Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant dilated cardiomyopathy (PMID: 12920062, 18795223, 19318026, 27532257, 29432544). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14504). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 23701190, 24386194, 29432544). For these reasons, this variant has been classified as Pathogenic. -

Long QT syndrome

Pathogenic:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PS4_Strong, PS3_Supporting, PM1, PM2, PP3 -

Cardiovascular phenotype

Pathogenic:1

Dec 19, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E161K pathogenic mutation (also known as c.481G>A), located in coding exon 2 of the LMNA gene, results from a G to A substitution at nucleotide position 481. The glutamic acid at codon 161 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in probands with a history of LMNA-related disease (Pasotti M et al. J Am Coll Cardiol, 2008 Oct;52:1250-60; Perrot A et al. Basic Res Cardiol, 2009 Jan;104:90-9; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Gigli M et al. J Am Coll Cardiol, 2019 Sep;74:1480-1490; Ferradini V et al. J Clin Med, 2021 Oct;10:; Ambry internal data). In addition, studies show this variant has an impact on protein function (Bhattacharjee P et al. Biochemistry, 2013 Jun;52:4229-41; Laurini E et al. Cardiovasc Res, 2018 May;114:846-857). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

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

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.6

H;.;H;H;H;.;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.7

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

REVEL

Pathogenic

0.74

Sift

Uncertain

0.014

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

Sift4G

Uncertain

0.057

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

Polyphen

0.89

P;.;P;P;.;.;D;.;.

Vest4

0.82

MutPred

0.84

Gain of MoRF binding (P = 0.0095);Gain of MoRF binding (P = 0.0095);Gain of MoRF binding (P = 0.0095);Gain of MoRF binding (P = 0.0095);Gain of MoRF binding (P = 0.0095);.;.;.;.;

MVP

0.99

MPC

1.6

ClinPred

0.99

GERP RS

5.6

Varity_R

0.59

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

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