rs267607578

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_170707.4(LMNA):c.1412G>A(p.Arg471His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,020 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R471C) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 7.81

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 19 ACMG points.

PM1

In a strand (size 5) in uniprot entity LMNA_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 chr1-156136951-C-T 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, 0.99

PP5

Variant 1-156136952-G-A is Pathogenic according to our data. Variant chr1-156136952-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156136952-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-156136952-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1412G>A	p.Arg471His	missense_variant	8/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4 linkuse as main transcript	c.1412G>A	p.Arg471His	missense_variant	8/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.1412G>A	p.Arg471His	missense_variant	8/12	1	NM_170707.4	ENSP00000357283	P1	P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.1412G>A	p.Arg471His	missense_variant	8/10		NM_005572.4	ENSP00000503633		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

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:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2024	Not observed at significant frequency in large population cohorts (gnomAD); 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: 20160190, 24846508, 29095976, 27532257, 33019804, 22177269, 24375749, 24623722, 22337857, 25569433, 22464770, 18585512, 18646565, 28663758, 29943882, 31729605, 31383942, 31983221, 24503780, 37652022, 23582089, 30078822, 33906374, 23054336, 34862408, 10939567) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 11, 2019	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 31, 2017	The p.Arg471His variant (rs267607578) is absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser, and has been observed in multiple cohorts of dilated cardiomyopathy (DCM)/muscular dystrophy patients (Astejada 2007, Larsen 2012, Parks 2008, Pugh 2014, van Rijsingen 2013, Walsh 2017). It is also classified in the ClinVar database as likely pathogenic by multiple clinical laboratories (Variation ID: 36476). While observed in several symptomatic individuals (and multiple pedigrees suggestive of dominantly inherited disease), this variant has not been shown to segregate with disease. Additionally, functional assays of p.Arg471His variant protein have yielded mixed results: overexpression of p.Arg471His in COS7 cells did not alter nuclear envelope architecture, as did the overexpression of other purportedly pathogenic LMNA variants (Cowan 2010). However, another assay examining the effect of pathogenic LMNA variants interactions between LMNA and various binding partners suggests that p.Arg471His disrupts approximately 12% of such interactions, whereas other more benign-learning variants disrupt fewer (Dittmer 2014). The arginine at codon 471 is highly conserved considering 12 species up to fruitfly (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on LMNA protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). Therefore, based on the available information, the p.Arg471His variant is likely to be pathogenic. -

Dilated cardiomyopathy 1A

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense variant. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000036476). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 18585512, 22177269, 23582089, 27532257, 29095976, 29943882). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 29943882). Different missense changes at the same codon (p.Arg471Cys, p.Arg471Gly) have been reported to be associated with LMNA-related disorder (ClinVar ID: VCV000014503 / PMID: 12768443, 18041775 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 09, 2021	- -
Pathogenic, criteria provided, single submitter	not provided	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	-	- -

Primary dilated cardiomyopathy

Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 20, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces arginine with histidine at codon 471 in the lamin tail domain of the LMNA 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). An experimental functional study using transfected COS7 cells has shown that this variant does not cause abnormal lamin A localization or morphology compared to wild-type (PMID: 20160190). Another experimental functional study using fibroblasts derived from heterozygous carrier individuals has shown that this variant causes increased lamin C isoform levels compared to lamin A isoform levels (PMID: 29943882). The clinical relevance of this observation is not known. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 18585512, 24503780, 25569433, 29095976, 29943882, 31983221, 35026164). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 29943882). This variant has also been reported in an individual affected with sudden unexplained death and suspected to be affected with dilated cardiomyopathy (PMID: 22177269). Additionally, this variant has been reported in individuals affected with laminopathy (PMID: 18646565, 28663758). 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 Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 21, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 28, 2011	The Arg471His variant has been reported in one individual with DCM and was absen t from 300 Caucasian control chromosomes, supporting a pathogenic role (Parks 20 08). Our laboratory has previously identified this variant in two affected indiv iduals (one with DCM, conduction system disease and skeletal myopathy and one wi th ventricular tachycardia) and was absent from 412 Caucasian and 354 Black cont rol chromosomes (LMM unpublished data). Furthermore, arginine (Arg) at amino aci d position 471 is conserved in evolutionarily distant species, suggesting that a change would not be tolerated. Finally, variants in LMNA have been identified i n a range of disorders including dilated cardiomyopathy with or without conducti on system disease, which is consistent with the features observed with this vari ant thus far. In summary, the data available so far suggests that the Arg471His variant is likely to be pathogenic. -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 471 of the LMNA protein (p.Arg471His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant dilated cardiomyopathy and limb-girdle muscular dystrophy (PMID: 18646565, 22177269, 23582089, 27532257, 29943882). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36476). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 20160190). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The p.R471H pathogenic mutation (also known as c.1412G>A), located in coding exon 8 of the LMNA gene, results from a G to A substitution at nucleotide position 1412. The arginine at codon 471 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with laminopathy and dilated cardiomyopathy (DCM), including some with conduction system disease (Astejada MN et al. Acta Myol. 2007; 26(3):159-64; Parks SB et al. Am Heart J. 2008;156(1):161-9; Larsen MK et al. Forensic Sci Int 2012;219(1-3):33-8; Miller EM et al. J Genet Couns. 2012;22(2):258-67; Pugh TJ et al. Genet Med 2014;16(8):601-8). In one family, this mutation was detected in a proband with DCM and co-segregated with disease in similarly affected family members across multiple generations (Al-Saaidi RA et al. Eur. J. Heart Fail., 2018 10;20:1404-1412). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on internal structural analysis, this variant lies in a structured domain and is predicted to be moderately disruptive (Magracheva E et al. Acta Crystallogr Sect F Struct Biol Cryst. 2009;65(Pt 7):665-70). 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

0.83

CardioboostCm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

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

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;M;M;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.5

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

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.051

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

Polyphen

1.0

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

Vest4

0.85

MutPred

0.96

Loss of MoRF binding (P = 0.0553);Loss of MoRF binding (P = 0.0553);Loss of MoRF binding (P = 0.0553);Loss of MoRF binding (P = 0.0553);.;.;.;.;

MVP

0.95

MPC

1.2

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.84

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