rs150840924

Positions:

chr1-156136359-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_170707.4(LMNA):c.1303C>T(p.Arg435Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,100 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. R435H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:7O:2

Conservation

PhyloP100: 1.96

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_170707.4

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

PP5

Variant 1-156136359-C-T is Pathogenic according to our data. Variant chr1-156136359-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66802.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=2, Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=6}. Variant chr1-156136359-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-156136359-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1303C>T	p.Arg435Cys	missense_variant	7/12	ENST00000368300.9
LMNA	NM_005572.4 linkuse as main transcript	c.1303C>T	p.Arg435Cys	missense_variant	7/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.1303C>T	p.Arg435Cys	missense_variant	7/12	1	NM_170707.4	P1	P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.1303C>T	p.Arg435Cys	missense_variant	7/10		NM_005572.4		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152252

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250034

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135450

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.0000253

AC:

AN:

1459848

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000306

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:7Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2023	Reported in the heterozygous state in individuals with DCM or other types of cardiomyopathy (PMID: 14684700, 30847666, 32880476); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest reduced LMNA expression (though not quantified) and impaired cellular interactions (PMID: 19842191, 23804595, 24623722, 30137533, 36301259, 36200863); This variant is associated with the following publications: (PMID: 24846508, 22991222, 26733286, 20662858, 24375749, 24623722, 23804595, 20155465, 23969228, 28663758, 23299917, 25637381, 19842191, 32799420, 32880476, 31383942, 30847666, 33038109, 32376792, 34862408, 30137533, 36301259, 35449878, 36200863, 10939567, 14684700) -

Primary dilated cardiomyopathy

Uncertain:3

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2017	The p.Arg435Cys variant in LMNA has been reported in the heterozygous state in 1 adult with DCM and subtle myopic findings (Vytopil 2003) and in the homozygous state in 3 infants with a progeroid syndrome and restrictive dermopathy/skin abn ormalities (Madej-Pilarczyk 2009, Youn 2010, Starke 2013). The 3 infants did not have any cardiovascular features nor did any nor did any of the heterozygous re latives who were tested except one family member had mild signs of hypertensive cardiac disease that was most likely age related. Western blot and tissue immuno -staining analyses revealed the Arg435Cys variant led to progressive loss of LMN A over time associated with increasing DNA double strand breaks and decreased re cruitment of P53 binding protein 1 (53BP1) to DNA-damage sites, suggesting delay ed DNA repair (Madej-Pilarczyk 2009, Starke 2013). This variant has also been id entified in 2/111156 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150840924). Computational pre diction tools and conservation analysis do not provide strong support for or aga inst an impact to the protein. In summary, while there is some suspicion for a pathogenic role in progeroid syndrome and/or dermatological abnormalities when p resent in homozygosity, the clinical significance of this variant is uncertain. In addition, there is limited information available to assess if this variant is disease-causing for cardiomyopathy when present in heterozygosity and therefore the clinical significance of this variant for cardiomyopathy is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 04, 2023	This missense variant replaces arginine with cysteine at codon 435 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). Functional studies have shown that this variant impairs protein interactions (PMID: 24623722) and the recruitment of P53 binding protein to DNA-damage sites indicating delayed DNA repair (PMID: 23804595). This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 14684700, 32880476), in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), and in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has also been reported in homozygous state in three infants affected with progeroid syndrome with restrictive dermopathy-like features (PMID: 19842191, 20662858, 23804595). Evaluation of these infants as well as ten heterozygous family members revealed no cardiological abnormalities except for one family member affected with probable age-related hypertensive cardiac disease (PMID: 23804595). A study using a skin sample from one of the infants showed that this variant was associated with decreased lamin A protein and increased DNA double strand breaks (PMID: 23804595). This variant has been identified in 2/250034 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While this variant has been observed in a few individuals affected with autosomal recessive progeroid syndrome, its role in autosomal dominant cardiovascular disorders is not clearly established. 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. -

Hutchinson-Gilford syndrome

Uncertain:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2017	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg435Cys variant in LMNA has been reported in the heterozygous state in 1 adult with DCM and subtle myopic findings (Vytopil 2003) and in the homozygous state in 3 infa nts with a progeroid syndrome and restrictive dermopathy/skin abnormalities (Mad ej-Pilarczyk 2009, Youn 2010, Starke 2013). The 3 infants did not have any cardi ovascular features nor did any nor did any of the heterozygous relatives who wer e tested except one family member had mild signs of hypertensive cardiac disease that was most likely age related. Western blot and tissue immuno-staining analy ses revealed the Arg435Cys variant led to progressive loss of LMNA over time ass ociated with increasing DNA double strand breaks and decreased recruitment of P5 3 binding protein 1 (53BP1) to DNA-damage sites, suggesting delayed DNA repair ( Madej-Pilarczyk 2009, Starke 2013). This variant has also been identified in 2/1 11156 of European chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs150840924). Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role in progeroid syndrome and/or dermatological abnormalities when present in homoz ygosity, the clinical significance of this variant is uncertain. In addition, th ere is limited information available to assess if this variant is disease-causin g for cardiomyopathy when present in heterozygosity and therefore the clinical s ignificance of this variant for cardiomyopathy is uncertain. -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 435 of the LMNA protein (p.Arg435Cys). This variant is present in population databases (rs150840924, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive progeroid restrictive dermopathy (PMID: 14684700, 19842191, 20662858, 23804595). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66802). 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%. Experimental studies have shown that this missense change affects LMNA function (PMID: 23804595, 24623722). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 27, 2023

This missense variant replaces arginine with cysteine at codon 435 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). Functional studies have shown that this variant impairs protein interactions (PMID: 24623722) and the recruitment of P53 binding protein to DNA-damage sites indicating delayed DNA repair (PMID: 23804595). This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 14684700, 32880476), in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), and in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has also been reported in homozygous state in three infants affected with progeroid syndrome with restrictive dermopathy-like features (PMID: 19842191, 20662858, 23804595). Evaluation of these infants as well as ten heterozygous family members revealed no cardiological abnormalities except for one family member affected with probable age-related hypertensive cardiac disease (PMID: 23804595). A study using a skin sample from one of the infants showed that this variant was associated with decreased lamin A protein and increased DNA double strand breaks (PMID: 23804595). This variant has been identified in 2/250034 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While this variant has been observed in a few individuals affected with autosomal recessive progeroid syndrome, its role in autosomal dominant cardiovascular disorders is not clearly established. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2023

The p.R435C variant (also known as c.1303C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1303. The arginine at codon 435 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the homozygous state in several probands with autosomal recessive progeria syndrome or restrictive dermopathy (Madej-Pilarczyk A et al. Am. J. Med. Genet. A, 2009 Nov;149A:2387-92; Starke S et al. Aging (Albany NY), 2013 Jun;5:445-59; Youn GJ et al. Clin. Genet., 2010 Aug;78:199-200). It has also been detected in the heterozygous state in cardiomyopathy cohorts and an arrhythmia cohort; however, clinical details were limited in these cases (Vytopil M et al. J. Med. Genet., 2003 Dec;40:e132; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). Functional studies suggest that this variant may impact protein-protein interactions, including BAF binding, and internal structural analysis indicates that this alteration disrupts disrupts the interface of LMNA with BAF (Dittmer TA et al. Mol. Biol. Cell, 2014 May;25:1493-510; Samson C et al. Nucleic Acids Res., 2018 11;46:10460-10473; Ambry internal data). However, the mechanism of pathogenicity for progeria syndrome is not well-established and the clinical significance of this impact is unclear. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive Hutchinson-Gilford progeria syndrome when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant laminopathies is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

CardioboostCm

Benign

0.013

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

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

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.77

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.5

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.95

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

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0040

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.97

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

Vest4

0.77

MVP

0.99

MPC

1.1

ClinPred

0.70

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.77

gMVP

0.93

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