1-156137207-C-T

Variant names:

• chr1-156137207-C-T
• rs57629361
• NM_170707.4:c.1583C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

The NM_170707.4(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. T528R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5 O:1
• Conservation: PhyloP100: 4.15
• Publications: 53 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: Likely_pathogenic. The variant received 9 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, 16 uncertain in NM_170707.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156137207-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 66850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 1-156137207-C-T is Pathogenic according to our data. Variant chr1-156137207-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 66851.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1583C>T	p.Thr528Met	missense_variant	Exon 9 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1583C>T	p.Thr528Met	missense_variant	Exon 9 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000933 AC: 2 AN: 214466 AF XY: 0.00000859

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 41648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25806

East Asian (EAS) AF: 0.00 AC: 0 AN: 38980

South Asian (SAS) AF: 0.00 AC: 0 AN: 84182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1104390

Other (OTH) AF: 0.00 AC: 0 AN: 59710

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000358 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Other:1

Nov 03, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 528 of the LMNA protein (p.Thr528Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive Hutchinson–Gilford progeria syndrome (PMID: 16825282, 37387251). This variant has been reported in individual(s) with familial partial lipodystrophy (PMID: 28641778); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 66851). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 22413764, 24623722, 26900797, 34862408). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Oct 18, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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), as well as being identified as homozygous in individuals with features consistent with Hutchinson–Gilford progeria syndrome (Saadi A et al. Am J Med Genet A, 2023 Sep;191:2274-2289). 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

May 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 528 of the lamin A/C proteins. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant causes abnormal nuclei with aggregates (PMID: 22413764, 30420677), nuclear rupture and loss of compartmentalization (PMID: 21831885). However, clinical relevance of these observations is not clear. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 30420677), in one individual affected with non-valvular atrial fibrillation (PMID: 22413764), and in one infant affected with sudden death (PMID: 28074886). It has also been reported in multiple individuals affected with familial partial lipodystrophy type 2 (PMID: 28641778, 33916827, 36397776). Additionally, this variant has 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

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.;.
PhyloP100		4.2
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
Mutation Taster		=0/100	disease causing

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: rs57629361; hg19: chr1-156106998;