NM_170707.4(LMNA):c.1303C>T (p.Arg435Cys) AND Primary dilated cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 23, 2017
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:: RCV000148606.15

Allele description [Variation Report for NM_170707.4(LMNA):c.1303C>T (p.Arg435Cys)]

NM_170707.4(LMNA):c.1303C>T (p.Arg435Cys)

Gene:

LMNA:lamin A/C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_170707.4(LMNA):c.1303C>T (p.Arg435Cys)

HGVS:

NC_000001.11:g.156136359C>T
NG_008692.2:g.58787C>T
NM_001257374.3:c.967C>T
NM_001282624.2:c.1060C>T
NM_001282625.2:c.1303C>T
NM_001282626.2:c.1303C>T
NM_005572.4:c.1303C>T
NM_170707.4:c.1303C>TMANE SELECT
NM_170708.4:c.1303C>T
NP_001244303.1:p.Arg323Cys
NP_001269553.1:p.Arg354Cys
NP_001269554.1:p.Arg435Cys
NP_001269555.1:p.Arg435Cys
NP_005563.1:p.Arg435Cys
NP_005563.1:p.Arg435Cys
NP_733821.1:p.Arg435Cys
NP_733822.1:p.Arg435Cys
LRG_254t1:c.1303C>T
LRG_254t2:c.1303C>T
LRG_254:g.58787C>T
LRG_254p1:p.Arg435Cys
LRG_254p2:p.Ala435Cys
NC_000001.10:g.156106150C>T
NM_001257374.1:c.967C>T
NM_005572.3:c.1303C>T
NM_170707.2:c.1303C>T
NM_170707.3:c.1303C>T
NP_733821.1:p.Ala435Cys
NP_733821.1:p.Ala435Cys
P02545:p.Arg435Cys

Protein change:

R323C

Links:

UniProtKB: P02545#VAR_039779; dbSNP: rs150840924

NCBI 1000 Genomes Browser:

rs150840924

Molecular consequence:

NM_001257374.3:c.967C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1060C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1303C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1303C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1303C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1303C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1303C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000190321	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV000198614	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (May 23, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14684700, 19842191, 20662858, 23804595, 24375749, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190321

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV000198614

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(May 23, 2017)

germline

clinical testing

PubMed (6)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes.

Vytopil M, Benedetti S, Ricci E, Galluzzi G, Dello Russo A, Merlini L, Boriani G, Gallina M, Morandi L, Politano L, Moggio M, Chiveri L, Hausmanova-Petrusewicz I, Ricotti R, Vohanka S, Toman J, Toniolo D.

J Med Genet. 2003 Dec;40(12):e132. No abstract available.

PubMed [citation]

PMID:: 14684700
PMCID:: PMC1735334

Progeroid syndrome with scleroderma-like skin changes associated with homozygous R435C LMNA mutation.

Madej-Pilarczyk A, Rosińska-Borkowska D, Rekawek J, Marchel M, Szaluś E, Jabłońska S, Hausmanowa-Petrusewicz I.

Am J Med Genet A. 2009 Nov;149A(11):2387-92. doi: 10.1002/ajmg.a.33018.

PubMed [citation]

PMID:: 19842191

See all PubMed Citations (6)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190321.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000198614.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Arg435Cys variant in LMNA has been reported in the heterozygous state in 1 adult with DCM and subtle myopic findings (Vytopil 2003) and in the homozygous state in 3 infants with a progeroid syndrome and restrictive dermopathy/skin abn ormalities (Madej-Pilarczyk 2009, Youn 2010, Starke 2013). The 3 infants did not have any cardiovascular features nor did any nor did any of the heterozygous re latives who were tested except one family member had mild signs of hypertensive cardiac disease that was most likely age related. Western blot and tissue immuno -staining analyses revealed the Arg435Cys variant led to progressive loss of LMN A over time associated with increasing DNA double strand breaks and decreased re cruitment of P53 binding protein 1 (53BP1) to DNA-damage sites, suggesting delay ed DNA repair (Madej-Pilarczyk 2009, Starke 2013). This variant has also been id entified in 2/111156 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150840924). Computational pre diction tools and conservation analysis do not provide strong support for or aga inst an impact to the protein. In summary, while there is some suspicion for a pathogenic role in progeroid syndrome and/or dermatological abnormalities when p resent in homozygosity, the clinical significance of this variant is uncertain. In addition, there is limited information available to assess if this variant is disease-causing for cardiomyopathy when present in heterozygosity and therefore the clinical significance of this variant for cardiomyopathy is uncertain.

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

Last Updated: Apr 6, 2024

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