rs267607578

Positions:

• chr1-156136952-G-A
• chr1-156136952-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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 Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 7.81

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14503.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, not_provided=1, Likely_pathogenic=3, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, LMNA
• 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	UniProt
LMNA	NM_170707.4	c.1412G>A	p.Arg471His	missense_variant	8/12	ENST00000368300.9
LMNA	NM_005572.4	c.1412G>A	p.Arg471His	missense_variant	8/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1412G>A	p.Arg471His	missense_variant	8/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1412G>A	p.Arg471His	missense_variant	8/10		NM_005572.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32

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: 3 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727224

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: 2 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

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:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5 Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2023	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, 23582089, 30078822, 33906374, 23054336, 34862408, 10939567) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 11, 2019	- -

Dilated cardiomyopathy 1A Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 09, 2021	- -
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. -
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	Blueprint Genetics	Aug 21, 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	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

Invitae

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	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
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	T
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	D
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

Other links and lift over

dbSNP: rs267607578; hg19: chr1-156106743; COSMIC: COSV61542545; COSMIC: COSV61542545;