chr1-156137204-G-C

Variant names:

• chr1-156137204-G-C
• rs57520892
• NM_170707.4:c.1580G>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_170707.4(LMNA):​c.1580G>C​(p.Arg527Pro) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R527L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 5.39
• Publications: 109 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• familial partial lipodystrophy, Dunnigan type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Hutchinson-Gilford progeria syndrome

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• restrictive dermopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
• Emery-Dreifuss muscular dystrophy 2, autosomal dominant

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• atrioventricular block

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• heart-hand syndrome, Slovenian type

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• Charcot-Marie-Tooth disease type 2B1

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 3, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mandibuloacral dysplasia with type A lipodystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• atrial fibrillation

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• atypical Werner syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy due to LMNA mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal restrictive dermopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LMNA-related cardiocutaneous progeria syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Emery-Dreifuss muscular dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal semi-dominant severe lipodystrophic laminopathy

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 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 chr1-156137204-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 919926.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 1-156137204-G-C is Pathogenic according to our data. Variant chr1-156137204-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170707.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	NM_170707.4	MANE Select	c.1580G>C	p.Arg527Pro	missense	Exon 9 of 12	NP_733821.1
	LMNA	NM_005572.4	MANE Plus Clinical	c.1580G>C	p.Arg527Pro	missense	Exon 9 of 10	NP_005563.1
	LMNA	NM_001406985.1		c.1580G>C	p.Arg527Pro	missense	Exon 9 of 13	NP_001393914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	ENST00000368300.9	TSL:1 MANE Select	c.1580G>C	p.Arg527Pro	missense	Exon 9 of 12	ENSP00000357283.4
	LMNA	ENST00000677389.1	MANE Plus Clinical	c.1580G>C	p.Arg527Pro	missense	Exon 9 of 10	ENSP00000503633.1
	LMNA	ENST00000368299.7	TSL:1	c.1580G>C	p.Arg527Pro	missense	Exon 9 of 12	ENSP00000357282.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial partial lipodystrophy, Dunnigan type Pathogenic:2

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LMNA c.1580G>C(p.Arg527Pro) variant has been reported in individuals affected with lipodystrophy (Kooi et al., 2002). Experimental studies have shown that an abnormal phenotype was seen in transfected cells with the R527P variant: nuclear aggregates of lamin A and displacement to cytoplasmic aggregates. This variant has been reported to affect LMNA protein function (Motsch et al., 2005). The p.Arg527Pro variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic. The variant affects a highly conserved arginine residue. This sequence change replaces arginine with proline at codon 527 of the LMNA protein (p.Arg527Pro) and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg527Pro in LMNA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1 Other:1

Nov 25, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 527 of the LMNA protein (p.Arg527Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant muscular dystrophies (PMID: 10080180, 19084400, 20980393). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14481). 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: 16218190, 19933576). This variant disrupts the p.Arg527 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12075506, 14627682, 18604166, 19432833, 23497705, 25286833, 25324471, 25823658). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Primary dilated cardiomyopathy Pathogenic:1

Feb 26, 2021

Loeys Lab, Universiteit Antwerpen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a missense variant in the LMNA gene (p.(Arg527Pro)). (PP2; based on GnomAd constraint matrix). This variant is absent from population databases such as GnomAD (PM2) . This variant has been described in literature (PMID: 16218190; PMID: 19933576) (PP1). An abnormal phenotype was seen in transfected cells with the R527P variant: nuclear aggregates of lamin A and displacement to cytoplasmic aggregates. Of the different LMNA variants studied in this paper, R527P produced the most severe phenotype on cellular level (PMID: 19933576) (PS3). The variant has been described in several individuals and families affected with AD muscular dystrophies and segregated with the disease in these families (PMID: 10080180, 19084400, 20980393).The variant affects a highly conserved amino acid. Other variants that disrupt this amino acid have been reported as pathogenic p.Arg527His (PMID: 12075506, 14627682, 18604166, 25823658, 25324471) and p.Arg527Cys (PMID:19432833, 23497705, 25286833) (PM5). We identified this variant in a patients with DCM. In conclusion this variant was classified as pathogenic according to ACMG-guidelines (PS3, PM2,PM5,PP1,PP2).

Cardiovascular phenotype Pathogenic:1

Oct 16, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R527P pathogenic mutation (also known as c.1580G>C), located in coding exon 9 of the LMNA gene, results from a G to C substitution at nucleotide position 1580. The arginine at codon 527 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in numerous individuals with laminopathies, including muscular dystrophies, and segregated with disease in some families (Bonne G et al. Nat Genet, 1999 Mar;21:285-8; van der Kooi AJ et al. Neurology, 2002 Aug;59:620-3; Mitsuhashi H et al. J Cell Sci, 2010 Nov;123:3893-900; van Rijsingen IA et al. Eur J Heart Fail, 2013 Apr;15:376-84; Tan D et al. PLoS One, 2015 Jun;10:e0129699; Ben Yaou R et al. Brain Commun, 2021 Jul;3:fcab075; Fan Y et al. J Med Genet, 2021 May;58:326-333; Vasandani C et al. J Endocr Soc, 2022 Oct;6:bvac155). Additionally, this alteration was detected as de novo in two siblings with muscular dystrophy (Makri S et al. Neuromuscul Disord, 2009 Jan;19:26-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Emery-Dreifuss muscular dystrophy 2, autosomal dominant Pathogenic:1

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.71
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.13	T
Polyphen		0.97	D
Vest4		0.91
MutPred		0.66		Loss of MoRF binding (P = 0.0127)
MVP		0.99
MPC		0.64
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs57520892; hg19: chr1-156106995;