Variant NM_170707.4:c.1146C>T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_170707.4(LMNA):c.1146C>T(p.Gly382Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G382G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

LMNA
NM_170707.4 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 0.481

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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-156136110-C-T is Pathogenic according to our data. Variant chr1-156136110-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156136110-C-T is described in Lovd as [Pathogenic]. Variant chr1-156136110-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4 link	c.1146C>T	p.Gly382Gly	synonymous_variant	Exon 6 of 12	ENST00000368300.9	NP_733821.1	P02545-1A0A384MQX1
LMNA	NM_005572.4 link	c.1146C>T	p.Gly382Gly	synonymous_variant	Exon 6 of 10	ENST00000677389.1	NP_005563.1	P02545-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 link	c.1146C>T	p.Gly382Gly	synonymous_variant	Exon 6 of 12	1	NM_170707.4	ENSP00000357283.4		P02545-1
LMNA	ENST00000677389.1 link	c.1146C>T	p.Gly382Gly	synonymous_variant	Exon 6 of 10		NM_005572.4	ENSP00000503633.1		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152140

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7Other:1

Jan 03, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in association with limb-girdle muscular dystrophy, arrhythmia, and dilated cardiomyopathy (DCM) in individuals referred for genetic testing at GeneDx and in the published literature (PMID: 24503780, 17377071); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, predict the creation of a strong cryptic splice donor site upstream of the natural donor site in intron 6; Published mRNA functional studies demonstrated creation of a cryptic splice donor site in the 3' end of exon 6, resulting in a deletion of the last 13 nucleotides of exon 6 and a premature stop codon 93 amino acids downstream (PMID: 17377071); This variant is associated with the following publications: (PMID: 27506821, 24915601, 28679633, 28798025, 29582363, 31447099, Ferradini2021[publication], 24503780, 17377071) -

May 24, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LMNA: PVS1:Strong, PM2, PS4:Moderate, PS3:Supporting -

Jun 02, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy;C0027868:Neuromuscular disease

Pathogenic:1

May 25, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly382Gly variant in LMNA has been previously reported in 1 individual wit h LVNC, 2 individuals with DCM and conduction system disease, and 1 individual w ith childhood-onset limb-girdle muscular dystrophy and adult-onset DCM with SVT (Benedetti 2007, Di Resta 2014, Ito 2017, Miszalski-Jamka 2017, LMM Data). It al so segregated with DCM in 2 affected relative. This variant has also been report ed by other clinical laboratories in ClinVar (Variation ID: 48032). This variant was absent from large population studies. This variant does not alter the amino acid residue, but RNA studies showed that it creates a new splice site in the 3 ' end of exon 6 resulting in the deletion of the remaining 13 bases in this exon (Benedetti 2007, Di Resta 2014). This deletion causes a frameshift, altering th e protein's amino acid sequence beginning at codon 383 and leading to a prematur e stop codon 93 amino acids downstream, which is predicted to lead to a truncate d or absent protein. In summary, although additional studies are required to ful ly establish its clinical significance, the p.Gly382Gly variant is likely pathog enic. ACMG/AMP criteria applied: PS3, PM2, PS4_Supporting. -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 382 of the LMNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LMNA protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with cardiomyopathy and conduction disease and/or limb-girdle muscular dystrophy (PMID: 17377071, 27506821; internal data). ClinVar contains an entry for this variant (Variation ID: 48032). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1A

Pathogenic:1

Apr 27, 2021

Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Sep 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1146C>T pathogenic mutation (also known as p.G382G) is located in coding exon 6 of the LMNA gene. This variant results from a C to T substitution at nucleotide position 1146. This nucleotide substitution does not change the amino acid at codon 382. This variant has been reported in multiple individuals with phenotypes consistent with laminopathies including limb-girdle muscular dystrophy, dilated cardiomyopathy (DCM), and cardiac conduction disease and/or arrhythmia (Benedetti S et al. Neurology, 2007 Sep;69:1285-92; Di Resta C et al. Clin. Chim. Acta, 2014 Sep;436:276-82; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; external communication, Ambry internal data). Published RNA studies have demonstrated that this variant causes abnormal splicing leading to a frameshift and premature stop codon (Benedetti S et al. Neurology, 2007 Sep;69:1285-92; Di Resta C et al. Clin. Chim. Acta, 2014 Sep;436:276-82). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: -2

DS_DL_spliceai

0.87

Position offset: 11

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