rs373671419

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBP6

The NM_170707.4(LMNA):c.1657G>A(p.Asp553Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000296 in 1,555,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. D553H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 5.27

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:

LMNA (HGNC:):

LMNA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.09031206).

BP6

Variant 1-156137702-G-A is Benign according to our data. Variant chr1-156137702-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286258.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1657G>A	p.Asp553Asn	missense_variant	10/12	ENST00000368300.9	NP_733821.1	P02545-1A0A384MQX1
LMNA	NM_005572.4 linkuse as main transcript	c.1657G>A	p.Asp553Asn	missense_variant	10/10	ENST00000677389.1	NP_005563.1	P02545-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.1657G>A	p.Asp553Asn	missense_variant	10/12	1	NM_170707.4	ENSP00000357283.4		P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.1657G>A	p.Asp553Asn	missense_variant	10/10		NM_005572.4	ENSP00000503633.1		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000984

AC:

AN:

162670

Hom.:

AF XY:

0.000128

AC XY:

AN XY:

85804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000602

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:

0.0000155

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1403638

Hom.:

Cov.:

AF XY:

0.0000245

AC XY:

AN XY:

692560

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000446

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:

0.00000555

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.000151

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000136

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.00000960

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published in association with an LMNA-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 10939567, 28679633, 27884249) -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2024	Variant summary: LMNA c.1657G>A (p.Asp553Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 1549110 control chromosomes, predominantly at a frequency of 0.00074 within the Latino subpopulation in the gnomAD database (v4.1 dataset). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in LMNA causing Cardiomyopathy phenotype (0.00025). c.1657G>A has been reported in the literature in individuals affected with cardiomyopathy and (suspected) muscular dystrophy (e.g. Kumar_2016, Nallamilli_2018), however no supportive evidence for causality was provided. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27884249, 30564623). ClinVar contains an entry for this variant (Variation ID: 286258). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 10, 2019	The p.Asp553Asn variant in LMNA is classified as likely benign because it has been identified in 0.06% (15/24926) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, 2 mammals (rat and mouse) have an asparagine (Asn) at this position despite relatively nearby amino acid conservation. In addition, most computational tools do not suggest a high likelihood of impact to the protein. ACMG/AMP Criteria applied: BS1_supporting, BP4. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Nov 29, 2016

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2024

The p.D553N variant (also known as c.1657G>A), located in coding exon 10 of the LMNA gene, results from a G to A substitution at nucleotide position 1657. The aspartic acid at codon 553 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in a ventricular tachycardia cohort (Kumar S et al. Circ Arrhythm Electrophysiol, 2016 08;9:; Kumar S et al. J Am Coll Cardiol, 2016 Nov;68:2299-2307). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 18, 2019

- -

Charcot-Marie-Tooth disease type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

CardioboostCm

Benign

0.015

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;.;T;.;.;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.090

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.090

T;T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.9

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

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.83

N;.;N;N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.17

T;.;D;T;T;T;T

Sift4G

Benign

0.16

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

Polyphen

0.88

P;.;D;.;.;B;.

Vest4

0.39

MVP

0.77

MPC

0.35

ClinPred

0.059

GERP RS

4.7

Varity_R

0.056

gMVP

0.42

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