Variant 1-156135268-C-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr1-156135269-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2159261.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

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, 0.99

PP5

Variant 1-156135268-C-T is Pathogenic according to our data. Variant chr1-156135268-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14498.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=10, Uncertain_significance=4}. Variant chr1-156135268-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.892C>T	p.Arg298Cys	missense_variant	5/12	ENST00000368300.9
LMNA	NM_005572.4 linkuse as main transcript	c.892C>T	p.Arg298Cys	missense_variant	5/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.892C>T	p.Arg298Cys	missense_variant	5/12	1	NM_170707.4	P1	P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.892C>T	p.Arg298Cys	missense_variant	5/10		NM_005572.4		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152244

Hom.:

0

Cov.:

32

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000359

AC:

9

AN:

250398

Hom.:

0

AF XY:

0.0000442

AC XY:

6

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

64

AN:

1461272

Hom.:

0

Cov.:

34

AF XY:

0.0000399

AC XY:

29

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

4

AN:

152244

Hom.:

0

Cov.:

32

AF XY:

0.0000269

AC XY:

2

AN XY:

74378

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:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000688

Hom.:

0

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

5

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2023	Published functional studies demonstrate a damaging effect as cells from R298C homozygous knock in mice showed downregulation of LMNA at both the protein and mRNA level (Poitelon et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12467734, 14607793, 11799477, 18549403, 17347251, 17536044, 35383421, 16809772, 10939567, 30340945, 34862408, 35449878, 22331516, 31383942) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Charcot-Marie-Tooth disease type 2B1

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 18, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 20, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 02, 2023	The observed missense c.344T>C(p.Leu115Pro) variant in GABRB2 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Leu115Pro variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on GABRB2 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 115 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 298 of the LMNA protein (p.Arg298Cys). This variant is present in population databases (rs59885338, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 14607793, 17347251, 18549403). It is commonly reported in individuals of North African ancestry (PMID: 11799477, 14607793, 17347251, 18549403). ClinVar contains an entry for this variant (Variation ID: 14498). 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%. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The p.R298C pathogenic mutation (also known as c.892C>T), located in coding exon 5 of the LMNA gene, results from a C to T substitution at nucleotide position 892. The arginine at codon 298 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in multiple homozygous individuals with autosomal recessive Charcot-Marie-Tooth disease, has shown segregation with disease in multiple families of Algerian or Moroccan descent, and has been described as a north western African founder mutation (Tazir M et al. Brain, 2004 Jan;127:154-63; Chaouch M et al. Neuromuscul Disord, 2003 Jan;13:60-7; Bouhouche A et al. Brain, 2007 Apr;130:1062-75; Hamadouche T et al. Ann Hum Genet, 2008 Sep;72:590-7). In vitro studies indicate this variant may impact protein function and lead to abnormal nuclear aggregates in some mammalian cell lines (Dreuillet C et al. Biol Cell, 2008 Jan;100:51-61; Anderson CL et al. NPJ Genom Med, 2021 Dec;6:103). 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 autosomal recessive Charcot-Marie-Tooth disease when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant cardiomyopathy and other laminopathies is unclear. -

Autosomal recessive axonal hereditary motor and sensory neuropathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 02, 2018

The p.Arg298Cys variant in LMNA has been reported as homozygous in at least 25 N orth African consanguineous families with clinical features of Charcot Marie Too th Disease variant 2B1 (CMT2B1) and has been described as a founder variant in t his population (De Sandre-Giovannoli 2002, Chaouch 2003, Bouhouche 2007, Ben Yao u 2007, Hamadouche 2008). Animal models of this homozygous variant are associate d with some molecular findings but not the phenotypic abnormalities seen in CMT2 B1 patients (Poitelon 2012). This variant has been identified in 6/1111132 of Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs59885338) and reported in ClinVar (Variation ID# 14498) ; however its frequency is low enough to be consistent with a recessive carrier frequency. In addition, computational prediction tools and conservation analysis suggest that the p.Arg298Cys variant may impact the protein. In summary, this v ariant meets criteria to be classified as pathogenic for CMT2B1 in an autosomal recessive manner based upon segregation studies, low frequency in controls, and functional evidence. ACMG/AMP Criteria applied: PS4; PP1_Strong; PM2_Supporting; PP3. -

Hutchinson-Gilford syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Color Diagnostics, LLC DBA Color Health

May 15, 2023

This missense variant replaces arginine with cysteine at codon 298 of the lamin A/C proteins. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant is a well-known founder mutation in North African countries and has been reported to segregate with autosomal recessive Charcot-Marie-Tooth type 2 in affected families (PMID: 11799477, 12467734, 14607793, 17347251; Clinvar variation ID: 14498). Cardiac systems were normal in all of over 20 homozygotes assessed (PMID: 12467734, 14607793). Over 40 heterozygous carriers were reported from these families, who were all asymptomatic except for one individual with nonspecific cardiac abnormalities (PMID: 17536044). This variant has also been reported in another two heterozygous individuals referred for cardiac catheterization (PMID: 32792077). This variant has been identified in 9/250398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive Charcot-Marie-Tooth type 2 (ClinVar variation ID:14498). -

Familial partial lipodystrophy, Dunnigan type

Uncertain:1

Uncertain significance, flagged submission

clinical testing

New York Genome Center

Dec 17, 2020

The heterozygous c.892C>T (p.Arg298Cys) variant in LMNA is a known pathogenic variant for autosomal recessive Charcot-Marie-Tooth disease, type 2B1(CMT2B1), and has been reported as homozygous in multiple consanguineous families affected with CMT2B1 [PMID: 11799477;PMID: 14607793;PMID: 12467734]. Family-members carrying heterozygous p.Arg298Cys variant were apparently normal [PMID: 11799477;PMID: 14607793;PMID: 12467734]. The variant has been reported in ClinVar database as pathogenic for recessive CMT2B1 disease [Variation ID:14498]. The p.Arg298Cys variant has 0.00002627 allele frequency in the gnomAD(v3) database (4 out of 152,244 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the general population. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools. Given that heterozygous carriers of p.Arg298Cys were apparently normal, and due to the absence of evidence supporting its pathogenicity in heterozygous state, the p.Arg298Cys variant in the LMNA gene is reported as a variant of uncertain significance for autosomal dominant familial partial lipodystrophy. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, flagged submission

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces arginine with cysteine at codon 298 of the lamin A/C proteins. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant is a well-known founder mutation in North African countries and has been reported to segregate with autosomal recessive Charcot-Marie-Tooth type 2 in affected families (PMID: 11799477, 12467734, 14607793, 17347251; Clinvar variation ID: 14498). Cardiac systems were normal in all of over 20 homozygotes assessed (PMID: 12467734, 14607793). Over 40 heterozygous carriers were reported from these families, who were all asymptomatic except for one individual with nonspecific cardiac abnormalities (PMID: 17536044). This variant has also been reported in another two heterozygous individuals referred for cardiac catheterization (PMID: 32792077). This variant has been identified in 9/250398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive Charcot-Marie-Tooth type 2 (ClinVar variation ID:14498). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

CardioboostCm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.34

D

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

32

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.84

D

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.92

D

MutationAssessor

Pathogenic

3.2

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.78

T

PROVEAN

Pathogenic

-7.6

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

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.89

MutPred

0.85

Loss of MoRF binding (P = 0.0116);Loss of MoRF binding (P = 0.0116);Loss of MoRF binding (P = 0.0116);Loss of MoRF binding (P = 0.0116);Loss of MoRF binding (P = 0.0116);.;.;.;

MVP

0.96

MPC

2.1

ClinPred

0.99

D

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.81

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.

1-156135268-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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