chr1-156137207-C-T

Position:

• chr1-156137207-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The ENST00000368300.9(LMNA):​c.1583C>T​(p.Thr528Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000159 in 1,443,324 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. T528K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: LMNA ENST00000368300.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 O:1
• Conservation: PhyloP100: 4.15

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 11 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, 8 uncertain in ENST00000368300.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156137207-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1583C>T	p.Thr528Met	missense_variant	9/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1583C>T	p.Thr528Met	missense_variant	9/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1583C>T	p.Thr528Met	missense_variant	9/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.1583C>T	p.Thr528Met	missense_variant	9/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000933 AC: 2 AN: 214466 Hom.: 0 AF XY: 0.00000859 AC XY: 1 AN XY: 116386

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: 0.0000209

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1443324 Hom.: 0 Cov.: 32 AF XY: 0.0000181 AC XY: 13 AN XY: 716866

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: 0.00

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000222 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The p.T528M variant (also known as c.1583C>T), located in coding exon 9 of the LMNA gene, results from a C to T substitution at nucleotide position 1583. The threonine at codon 528 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in individuals with laminopathies, including cardiac conduction disease, cardiomyopathy, and lipodystrophy (Saj M et al. Mol Diagn Ther, 2012 Apr;16:99-107; Akinci B et al. Metabolism, 2017 Jul;72:109-119; Neubauer J et al. Eur J Hum Genet, 2017 Apr;25:404-409; van Tienen FHJ et al. Eur J Hum Genet, 2019 Mar;27:389-399; Araújo-Vilar D et al. J Clin Med, 2021 Apr;10:[ePub ahead of print]; Vasandani C et al. J Endocr Soc, 2022 Oct;6:bvac155). Additionally, this alteration has been identified in a case report of a proband who was compound heterozygous with an additional alteration in LMNA, who had classical symptoms of Hutchinson–Gilford progeria syndrome (Verstraeten VL et al. Hum Mol Genet, 2006 Aug;15:2509-22). Two other alterations at the same codon, p.T528R (c.1583C>G) and p.T528K (c.1583C>A), have been detected in numerous individuals with laminopathies, including individuals with Emery Dreifuss muscular dystrophy (EDMD) (Vytopil M et al. J Med Genet, 2003 Dec;40:e132; Scharner J et al. Hum Mutat, 2011 Feb;32:152-67; Zhang L et al. Mol Med Rep, 2015 Oct;12:5065-71; Lee Y et al. J Clin Neurol, 2017 Oct;13:405-410; Sivitskaya LN et al. Acta Myol, 2017 Dec;36:207-212; Stehlíková K et al. Clin Genet, 2017 Mar;91:463-469; Peretto G et al. Ann Intern Med, 2019 Oct;171:458-463; Ben Yaou R et al. Brain Commun, 2021 Jul;3:fcab075). This amino acid position is highly 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 laminopathies; however, its clinical significance for Hutchinson–Gilford progeria syndrome is unclear. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 12, 2020

This missense variant replaces threonine with methionine at codon 528 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes abnormal nuclei with aggregates (PMID: 22413764), nuclear rupture and loss of compartmentalization (PMID: 21831885). However, clinical relevance of these observations is not clear. This variant has been reported in an individual affected with non-valvular atrial fibrillation (PMID: 22413764), as well as in an individual affected with familial partial lipodystrophy (PMID: 28641778). This variant has also been reported in compound heterozygous state with other variants in the LMNA gene in individuals affected with Hutchinson-Gilford progeria syndrome (PMID: 16825282), familial partial lipodystrophy (PMID: 15298354, 29078011), or mandibuloacral dysplasia with type A lipodystrophy (Xiang et al., 2014). Heterozygous carriers of this variant in these families were reported to be unaffected. This variant has been identified in 2/214466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While this variant has been observed in multiple individuals affected with laminopathy, the available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 01, 2023

This missense variant replaces threonine with methionine at codon 528 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes abnormal nuclei with aggregates (PMID: 22413764), nuclear rupture and loss of compartmentalization (PMID: 21831885). However, clinical relevance of these observations is not clear. This variant has been reported in an individual affected with non-valvular atrial fibrillation (PMID: 22413764), as well as in an individual affected with familial partial lipodystrophy (PMID: 28641778). This variant has also been reported in compound heterozygous state with other variants in the LMNA gene in individuals affected with Hutchinson-Gilford progeria syndrome (PMID: 16825282), familial partial lipodystrophy (PMID: 15298354, 29078011), or mandibuloacral dysplasia with type A lipodystrophy (Xiang et al., 2014). Heterozygous carriers of this variant in these families were reported to be unaffected. This variant has been identified in 2/214466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While this variant has been observed in multiple individuals affected with laminopathy, the available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostCm	Uncertain	0.80
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;.;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.2	D;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;T;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.;.
Vest4		0.89
MutPred		0.90		Gain of MoRF binding (P = 0.0819);.;Gain of MoRF binding (P = 0.0819);Gain of MoRF binding (P = 0.0819);Gain of MoRF binding (P = 0.0819);.;.;.;.;
MVP		0.99
MPC		1.1
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.90

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: rs57629361; hg19: chr1-156106998;