rs57830985

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP5

The NM_170707.4(LMNA):c.1745G>A(p.Arg582His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,584 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R582C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2O:1

Conservation

PhyloP100: 9.23

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr1-156138533-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 651240.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1, Pathogenic=2}.

PP2

Missense variant where missense usually causes diseases, LMNA

PP5

Variant 1-156138534-G-A is Pathogenic according to our data. Variant chr1-156138534-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14494.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, not_provided=1, Uncertain_significance=2, Likely_pathogenic=1}. Variant chr1-156138534-G-A is described in Lovd as [Pathogenic]. Variant chr1-156138534-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1745G>A	p.Arg582His	missense_variant	11/12	ENST00000368300.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.1745G>A	p.Arg582His	missense_variant	11/12	1	NM_170707.4	P1	P02545-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000824

AC:

AN:

242576

Hom.:

AF XY:

0.00000754

AC XY:

AN XY:

132586

show subpopulations

Gnomad AFR exome

AF:

0.0000665

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:

0.00000929

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460246

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726438

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000909

Hom.:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 582 of the LMNA protein (p.Arg582His). This variant is present in population databases (rs57830985, gnomAD 0.004%). This missense change has been observed in individuals with familial partial lipodystrophy (FPLD) (PMID: 10739751, 11231979, 20130076, 28641778). ClinVar contains an entry for this variant (Variation ID: 14494). 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. This variant disrupts the p.Arg582 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 22700598, 23783098), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

LMNA-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2023

The LMNA c.1745G>A variant is predicted to result in the amino acid substitution p.Arg582His. This variant has been reported in the heterozygous and homozygous states in multiple individuals with familial partial lipodystrophy (see for example, Garg et al. 2001. PubMed ID: 11231979; Akinci et al. 2017. PubMed ID: 28641778; Soyaltin et al. 2020. PubMed ID: 32685188). Different substitutions impacting the same amino acid (p.Arg582Cys, p.Arg582Ser) have also been reported in patients with partial lipodystrophy (Mory et al. 2012. PubMed ID: 22700598; Ji et al. 2013. PubMed ID: 23783098) This variant is reported in 0.0042% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-156108325-G-A). This variant is interpreted as pathogenic. -

Familial partial lipodystrophy, Dunnigan type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2001

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2021

The p.R582H variant (also known as c.1745G>A), located in coding exon 11 of the LMNA gene, results from a G to A substitution at nucleotide position 1745. The arginine at codon 582 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with atypical familial partial lipodystrophy (FPLD) in both the heterozygous and homozygous state, with severity of the disease correlated with zygosity (Garg A et al. J Clin Endocrinol Metab, 2001 Jan;86:59-65; Boschmann M et al. J Clin Endocrinol Metab, 2010 Apr;95:1634-43; Akinci B et al. Metabolism, 2017 07;72:109-119; Patni N et al. J Clin Endocrinol Metab, 2019 04;104:1099-1108; Soyaltin UE et al. Clin Diabetes Endocrinol, 2020 Jul;6:13). This variant has also been reported to segregate with disease (Speckman RA et al. Am J Hum Genet, 2000 Apr;66:1192-8; Akinci B et al. Metabolism, 2017 07;72:109-119). Another alteration at the same codon, p.R582C (c.1744C>T), has been similarly detected in the heterozygous and homozygous states in patients with FPLD (Mory PB et al. Eur J Endocrinol, 2012 Sep;167:423-31; Montenegro RM et al. Front Endocrinol (Lausanne), 2018 Aug;9:458). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 21, 2021

This missense variant replaces arginine with histidine at codon 582 of the lamin A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant represents a single nucleotide substitution in the 3' untranslated region of the lamin C transcript (ENST00000361308: :c.*770G>A). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. However, this variant has been reported in over 10 individuals affected with familial partial lipodystrophy (PMID: 10739751, 11231979, 20130076, 28641778, 30418556, 30595509, 32193531, 32685188). This variant has been identified in 3/273962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in multiple individuals affected with familial partial lipodystrophy, but 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 for autosomal dominant cardiomyopathy. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 15, 2023

This missense variant replaces arginine with histidine at codon 582 of the lamin A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant represents a single nucleotide substitution in the 3' untranslated region of the lamin C transcript (ENST00000361308: :c.*770G>A). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. However, this variant has been reported in over 10 individuals affected with familial partial lipodystrophy, which is a rare condition characterized by an abnormal distribution of fatty tissue in the body and associated with metabolic involvement, such as diabetes, hyperlipidemia, and hepatosteatosis (PMID: 10739751, 11231979, 20130076, 28641778, 30418556, 30595509, 32193531, 32685188). This variant has been identified in 3/273962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, the available evidence indicates that this variant is associated with familial partial lipodystrophy. However, the role of this variant in cardiomyopathy is not clear due to the lack of clinical evidence. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy. -

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

0.93

CardioboostCm

Uncertain

0.10

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.48

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.71

D;D;D;D;D;D

MetaSVM

Pathogenic

0.84

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.3

N;N;N;N;N;N

REVEL

Pathogenic

0.73

Sift

Uncertain

0.011

D;D;D;D;D;D

Sift4G

Uncertain

0.057

T;D;D;D;D;D

Polyphen

1.0

D;D;.;.;.;.

Vest4

0.73

MVP

0.96

MPC

1.2

ClinPred

0.61

GERP RS

5.0

Varity_R

0.21

gMVP

0.92

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

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