NM_170707.4:c.1477C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong

The NM_170707.4(LMNA):​c.1477C>T​(p.Gln493*) variant causes a stop gained change. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

LMNA
NM_170707.4 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 4.92

Publications

9 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: Pathogenic. The variant received 20 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 1-156137017-C-T is Pathogenic according to our data. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137017-C-T is described in CliVar as Pathogenic. Clinvar id is 14514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LMNANM_170707.4 linkc.1477C>T p.Gln493* stop_gained Exon 8 of 12 ENST00000368300.9 NP_733821.1 P02545-1A0A384MQX1
LMNANM_005572.4 linkc.1477C>T p.Gln493* stop_gained Exon 8 of 10 ENST00000677389.1 NP_005563.1 P02545-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LMNAENST00000368300.9 linkc.1477C>T p.Gln493* stop_gained Exon 8 of 12 1 NM_170707.4 ENSP00000357283.4 P02545-1
LMNAENST00000677389.1 linkc.1477C>T p.Gln493* stop_gained Exon 8 of 10 NM_005572.4 ENSP00000503633.1 P02545-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1Other:1
-
Epithelial Biology; Institute of Medical Biology, Singapore
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Jul 15, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24970098, 25525159, 25886484, 17136397, 32041989) -

Dilated cardiomyopathy 1A Pathogenic:1
Aug 21, 2024
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant has been identified by standard clinical testing. Selected ACMG criteria: Likely pathogenic (I):PM2;PVS1 -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant Pathogenic:1
Apr 01, 2007
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_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
56
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Uncertain
0.93
D
PhyloP100
4.9
Vest4
0.97
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.9
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
1.0
Position offset: -2

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

Publications

Other links and lift over

dbSNP: rs56699480; hg19: chr1-156106808; API