GeneBe

1-156138613-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 10P and 2B. PM2PP5_Very_StrongBP4BP7

The NM_170707.4(LMNA):​c.1824C>T​(p.Gly608Gly) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G608G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

LMNA
NM_170707.4 synonymous

Scores

2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:2

Conservation

PhyloP100: 0.203

Publications

480 publications found
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 Gene-Disease associations (from GenCC):
  • dilated cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • dilated cardiomyopathy 1A
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
  • familial partial lipodystrophy, Dunnigan type
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
  • Hutchinson-Gilford progeria syndrome
    Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • restrictive dermopathy 2
    Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
  • Emery-Dreifuss muscular dystrophy 2, autosomal dominant
    Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
  • atrioventricular block
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • heart-hand syndrome, Slovenian type
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
  • Charcot-Marie-Tooth disease type 2B1
    Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
  • Emery-Dreifuss muscular dystrophy 3, autosomal recessive
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • mandibuloacral dysplasia with type A lipodystrophy
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
  • atrial fibrillation
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • atypical Werner syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal dominant Emery-Dreifuss muscular dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy due to LMNA mutation
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • lethal restrictive dermopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • LMNA-related cardiocutaneous progeria syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal recessive Emery-Dreifuss muscular dystrophy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal semi-dominant severe lipodystrophic laminopathy
    Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-156138613-C-T is Pathogenic according to our data. Variant chr1-156138613-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.31). . Strength limited to SUPPORTING due to the PP5.
BP7
Synonymous conserved (PhyloP=0.203 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LMNANM_170707.4 linkc.1824C>T p.Gly608Gly synonymous_variant Exon 11 of 12 ENST00000368300.9 NP_733821.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LMNAENST00000368300.9 linkc.1824C>T p.Gly608Gly synonymous_variant Exon 11 of 12 1 NM_170707.4 ENSP00000357283.4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000229
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hutchinson-Gilford syndrome Pathogenic:4Other:1
-
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 01, 2009
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Feb 08, 2013
Genetic Services Laboratory, University of Chicago
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Sep 01, 2022
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Cryptic splice donor variant which results in abnormal splicing. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19172989 , 21875900). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 12714972 , 17459035 , 22611635). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12714972 , 17459035 , 22611635). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000014500 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3Other:1
Jul 01, 2013
Eurofins Ntd Llc (ga)
Significance: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 30, 2025
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

RNA studies demonstrate a damaging effect through a partial impact on splicing resulting in increased expression of truncated lamin A transcript with cell aging (PMID: 19172989); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24305605, 21251803, 12768443, 12702809, 22893709, 23969228, 22685055, 19172989, 23141186, 26670336, 15793835, 17459069, 17459035, 15982412, 30911407, 32297714, 36523395, 35801028, 16809772, 28679633, 31006814, 22611635, 17511383, 28878338, 33590899, 38191824, 21738662, 25946677, 32943904, 10939567, 21875900, 22148005, 20580717, 12714972, 25556323) -

May 26, 2021
AiLife Diagnostics, AiLife Diagnostics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1
Oct 08, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change affects codon 608 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 individual(s) with Hutchinson-Gilford progeria syndrome (HGPS) (PMID: 12714972, 12768443, 15793835, 17459035, 19172989, 22148005, 22611635, 22685055, 23141186, 25946677; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.2036C>T. ClinVar contains an entry for this variant (Variation ID: 14500). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LMNA function (PMID: 12714972, 19172989, 21875900, 22893709, 25567453). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy;C0033300:Hutchinson-Gilford syndrome Pathogenic:1
Feb 15, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Restrictive dermopathy 2 Pathogenic:1
Jul 01, 2009
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.31
CADD
Benign
16
DANN
Benign
0.91
PhyloP100
0.20
Mutation Taster
=98/2
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs58596362; hg19: chr1-156108404; API