1-156137204-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 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. R527C) 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:6 O:1
• Conservation: PhyloP100: 5.39

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 17 ACMG points.

• PM1: In a hotspot region, there are 5 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 chr1-156137203-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14487.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, not_provided=2, Uncertain_significance=2, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, LMNA
• 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 id is 14481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137204-G-C is described in Lovd as [Pathogenic]. Variant chr1-156137204-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1580G>C	p.Arg527Pro	missense_variant	9/12	ENST00000368300.9
LMNA	NM_005572.4	c.1580G>C	p.Arg527Pro	missense_variant	9/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1580G>C	p.Arg527Pro	missense_variant	9/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1580G>C	p.Arg527Pro	missense_variant	9/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial partial lipodystrophy, Dunnigan type Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2023

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). 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. 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

Pathogenic, criteria provided, single submitter

clinical testing

Loeys Lab, Universiteit Antwerpen

Feb 26, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2009

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.0	D;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0080	D;.;D;D;D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;D;D;D;D
Polyphen		0.97	D;.;P;D;.;.;P;.;.
Vest4		0.91
MutPred		0.66		Loss of MoRF binding (P = 0.0127);.;Loss of MoRF binding (P = 0.0127);Loss of MoRF binding (P = 0.0127);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

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: rs57520892; hg19: chr1-156106995;