NM_170707.4(LMNA):c.52_53dup (p.Thr19fs) AND Primary dilated cardiomyopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 31, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004004113.1

Allele description [Variation Report for NM_170707.4(LMNA):c.52_53dup (p.Thr19fs)]

NM_170707.4(LMNA):c.52_53dup (p.Thr19fs)

Genes:

LOC129931597:ATAC-STARR-seq lymphoblastoid silent region 1421 [Gene]
LMNA:lamin A/C [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_170707.4(LMNA):c.52_53dup (p.Thr19fs)

HGVS:

NC_000001.11:g.156114970_156114971dup
NG_008692.2:g.37398_37399dup
NM_001282625.2:c.52_53dup
NM_001282626.2:c.52_53dup
NM_005572.4:c.52_53dup
NM_170707.4:c.52_53dupMANE SELECT
NM_170708.4:c.52_53dup
NP_001269554.1:p.Thr19fs
NP_001269555.1:p.Thr19fs
NP_005563.1:p.Thr19fs
NP_733821.1:p.Thr19fs
NP_733822.1:p.Thr19fs
LRG_254:g.37398_37399dup
NC_000001.10:g.156084759_156084760insCT
NC_000001.10:g.156084761_156084762dup
NM_170707.3:c.52_53dupTC

Protein change:

T19fs

Links:

dbSNP: rs1553261855

NCBI 1000 Genomes Browser:

rs1553261855

Molecular consequence:

NM_001282625.2:c.52_53dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001282626.2:c.52_53dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_005572.4:c.52_53dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_170707.4:c.52_53dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_170708.4:c.52_53dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Primary dilated cardiomyopathy (DCM)
Synonyms:: Dilated Cardiomyopathy
Identifiers:: EFO: EFO_0000407; MONDO: MONDO:0005021; MeSH: D002311; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004826355	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 31, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11138304, 12854972, 12920062, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004826355

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(May 31, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation.

Bécane HM, Bonne G, Varnous S, Muchir A, Ortega V, Hammouda EH, Urtizberea JA, Lavergne T, Fardeau M, Eymard B, Weber S, Schwartz K, Duboc D.

Pacing Clin Electrophysiol. 2000 Nov;23(11 Pt 1):1661-6.

PubMed [citation]

PMID:: 11138304

Lamin A/C truncation in dilated cardiomyopathy with conduction disease.

MacLeod HM, Culley MR, Huber JM, McNally EM.

BMC Med Genet. 2003 Jul 10;4:4.

PubMed [citation]

PMID:: 12854972
PMCID:: PMC169171

See all PubMed Citations (4)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004826355.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The c.52_53dup (p.Thr19Profs*78) variant of the LMNA gene is located on the exon 1 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Thr19Profs*78), resulting in an absent or disrupted protein product. Loss-of-function variants in LMNA are known to be pathogenic and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with dilated cardiomyopathy (PMID: 11138304, 12854972, 12920062). The variant is reported in ClinVar (ID: 543212). This variant is absent in the general population database (gnomAD). Therefore, the c.52_53dup (p.Thr19Profs*78) variant of LMNA has been classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 1, 2024

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