rs56984562

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_170707.4(LMNA):c.1621C>A(p.Arg541Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R541P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 0.895

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 17 ACMG points.

PM1

In a domain LTD (size 117) in uniprot entity LMNA_HUMAN there are 96 pathogenic changes around while only 4 benign (96%) 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 chrnull-null-null-null is described in UniProt as null.

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, 0.924

PP5

Variant 1-156137666-C-A is Pathogenic according to our data. Variant chr1-156137666-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137666-C-A 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.1621C>A	p.Arg541Ser	missense_variant	10/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4 linkuse as main transcript	c.1621C>A	p.Arg541Ser	missense_variant	10/10	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.1621C>A	p.Arg541Ser	missense_variant	10/12	1	NM_170707.4	ENSP00000357283	P1	P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.1621C>A	p.Arg541Ser	missense_variant	10/10		NM_005572.4	ENSP00000503633		P02545-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1401750

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691498

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

ClinVar contains an entry for this variant (Variation ID: 66859). This missense change has been observed in individual(s) with dilated cardiomyopathy or limb-girdle muscular dystrophy (PMID: 16061563, 16537768, 20848652, 31498906). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 541 of the LMNA protein (p.Arg541Ser). 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg541 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14684700, 18564364, 18646565, 23183350, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 16061563, 16218190). -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 07, 2011

The Arg541Ser variant has been identified in at least 3 inidiviuals with DCM and was absent from 500 control chromosomes (Sylvuis 2005, Karkkainen 2006, Gupta 2010, Scharner 2011). One of these inidividuals was reported to have de novo occurance of this variant but no reference to ruling out non-medical explantations such as undisclosed adoption or non-paternity was mentioned in this article (Karkkainen 2006). In addition, this variant was reported in an individual with DCM but a family history of LGMD and DCM (Scharner 2011). Arginine (Arg) at position 541 is highly conserved across envolutionarily distant species, suggesting that a change may not be tolerated. Computational analysis (AlignGVGD, PolyPhen2, and SIFT) suggest that a change to a serine (Ser) at this position may impact the protien; however, the accuracy of such tools is unknown. In addition, changes to different amino acids at this position have been identified in individuals with muscular dystrophy (Arg541His, Arg541Pro) and DCM (Arg541Cys). Based on this information, the Arg541Ser variant is likely to be pathogenic. -

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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.92

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

L;.;L;L;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.0

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

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0040

D;T;D;D;D;D;D

Polyphen

0.99

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

Vest4

0.85

MutPred

0.76

Gain of ubiquitination at K542 (P = 0.044);.;Gain of ubiquitination at K542 (P = 0.044);Gain of ubiquitination at K542 (P = 0.044);.;.;.;

MVP

0.98

MPC

1.2

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.97

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