1-156136984-C-T

Position:

chr1-156136984-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong

The NM_170707.4(LMNA):c.1444C>T(p.Arg482Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,050 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R482L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 3.29

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a strand (size 3) in uniprot entity LMNA_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr1-156136985-G-T is described in Lovd as [Pathogenic].

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, 0.823

PP5

Variant 1-156136984-C-T is Pathogenic according to our data. Variant chr1-156136984-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156136984-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1444C>T	p.Arg482Trp	missense_variant	8/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4 linkuse as main transcript	c.1444C>T	p.Arg482Trp	missense_variant	8/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.1444C>T	p.Arg482Trp	missense_variant	8/12	1	NM_170707.4	ENSP00000357283	P1	P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.1444C>T	p.Arg482Trp	missense_variant	8/10		NM_005572.4	ENSP00000503633		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251272

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135826

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727230

show subpopulations

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:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2022	Recurrent pathogenic variant that has been reported in the heterozygous state in multiple individuals with partial lipodystrophy (PMID: 10655060); Multiple functional studies demonstrate that the R482W variant impairs the function of several lamin A interacting genes involved in adipogenesis and lipid metabolism (PMID: 25524705, 24108105); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27841971, 29438482, 29578370, 14510863, 26027246, 26756202, 34862408, 19574635, 21989830, 23846499, 25885670, 18396274, 23427149, 24108105, 20130076, 11344241, 19220582, 11792809, 14749366, 24375749, 26724531, 12669268, 26976018, 24002959, 27504462, 28751304, 28641778, 12524233, 17524034, 19622949, 16459536, 29108996, 30165155, 31194872, 29704234, 30954027, 31383942, 32041611, 33803652, 33502018, 10655060, 10939567, 25524705) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Familial partial lipodystrophy, Dunnigan type

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 14, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -

Charcot-Marie-Tooth disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 482 of the LMNA protein (p.Arg482Trp). This variant is present in population databases (rs57920071, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant familial partial lipodystrophy (PMID: 19622949, 25885670). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14489). 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 have shown that this missense change affects LMNA function (PMID: 19220582). This variant disrupts the p.Arg482 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10587585, 10999791, 19418082, 19859838, 20130076, 20625965, 26662654). 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. -

LMNA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2024

The LMNA c.1444C>T variant is predicted to result in the amino acid substitution p.Arg482Trp. This variant has been reported in the heterozygous state in many unrelated individuals and is the most common causative variant for familial partial lipodystrophy in the LMNA gene (Shackleton et al. 2000. PubMed ID: 10655060; Cao and Hegele. 2000. PubMed ID: 10587585; Belo et al. 2015. PubMed ID: 25885670; Vadrot et al. 2015. PubMed ID: 25524705; Vasandani et al. 2022. PubMed ID: 36397776). Functional studies indicate the p.Arg482Trp variant in the LMNA protein impairs the transcriptional activity of SREBP1 which plays a key role in lipid metabolism and adipocyte differentiation (Vadrot et al. 2015. PubMed ID: 25524705). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Based on the collective evidence, this variant is interpreted as pathogenic. -

Familial partial lipodystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Arg482Trp variant in LMNA has been reported in at least 12 European individuals with familial partial lipodystrophy, segregated with disease in at least 7 affected relatives from 2 families (PMID: 15531479, 10655060,11344241), and has been identified in 0.0009% (1/113640) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs57920071). This variant has also been reported in ClinVar as pathogenic (Variation ID: 14489). In vitro functional studies provide some evidence that the p.Arg482Trp variant may slightly impact protein function (PMID: 25524705). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic and one pathogenic variant, resulting in a different amino acid change at the same position, p.Arg482Leu and p.Arg482Gln, have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 10655060, 14597414, 19201734, 23313286, 10587585, 20130076, 28492532 /Variation ID: 14490 and 14486). In summary, this variant meets criteria to be classified as pathogenic for familial partial lipodystrophy in an autosomal dominant manner based on cosegregation with disease in multiple affected families and the prevalence of this variant in many affected individuals. ACMG/AMP Criteria applied: PP1_strong, PS4_moderate, PM5, PM2, PP3, PS3_supporting (Richards 2015). -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 01, 2022

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2018

The p.R482W pathogenic mutation (also known as c.1444C>T), located in coding exon 8 of the LMNA gene, results from a C to T substitution at nucleotide position 1444. The arginine at codon 482 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is a recurrent mutation that has been detected in numerous individuals with familial partial lipodystrophy (FPLD) and has been shown to segregate with disease in multiple families (Peters JM et al. Nat. Genet., 1998 Mar;18:292-5; Hegele RA et al. J. Clin. Endocrinol. Metab., 2000 Sep;85:3431-5; Speckman RA et al. Am. J. Hum. Genet., 2000 Apr;66:1192-8; Vigouroux C et al. Diabetes, 2000 Nov;49:1958-62; Schmidt HH et al. J. Clin. Endocrinol. Metab., 2001 May;86:2289-95; Vantyghem MC et al. J. Clin. Endocrinol. Metab., 2004 Nov;89:5337-46; Keller J et al. Obstet Gynecol, 2009 Aug;114:427-31; Nabrdalik K et al. Endokrynol Pol, 2013;64:306-11; Akinci B et al. Metab. Clin. Exp., 2017 07;72:109-119). Other alterations in the same codon, p.R482Q and p.R482L, have also been described in FPLD patients (Shackleton S et al. Nat. Genet., 2000 Feb;24:153-6). 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

0.92

CardioboostCm

Uncertain

0.16

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

.;.;D;.;.;.;.;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

M;M;M;M;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.8

D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;.;D;.;.

Vest4

0.77

MutPred

0.52

Loss of phosphorylation at T480 (P = 0.0671);Loss of phosphorylation at T480 (P = 0.0671);Loss of phosphorylation at T480 (P = 0.0671);Loss of phosphorylation at T480 (P = 0.0671);.;.;.;.;

MVP

0.97

MPC

1.1

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over