NM_170707.4(LMNA):c.607G>A (p.Glu203Lys) AND Primary dilated cardiomyopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 20, 2018
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:: RCV000211790.5

Allele description [Variation Report for NM_170707.4(LMNA):c.607G>A (p.Glu203Lys)]

NM_170707.4(LMNA):c.607G>A (p.Glu203Lys)

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.607G>A (p.Glu203Lys)

HGVS:

NC_000001.11:g.156134496G>A
NG_008692.2:g.56924G>A
NM_001257374.3:c.271G>A
NM_001282624.2:c.364G>A
NM_001282625.2:c.607G>A
NM_001282626.2:c.607G>A
NM_005572.4:c.607G>A
NM_170707.4:c.607G>AMANE SELECT
NM_170708.4:c.607G>A
NP_001244303.1:p.Glu91Lys
NP_001269553.1:p.Glu122Lys
NP_001269554.1:p.Glu203Lys
NP_001269555.1:p.Glu203Lys
NP_005563.1:p.Glu203Lys
NP_733821.1:p.Glu203Lys
NP_733822.1:p.Glu203Lys
LRG_254t2:c.607G>A
LRG_254:g.56924G>A
NC_000001.10:g.156104287G>A
NM_170707.2:c.607G>A
NM_170707.3:c.607G>A
P02545:p.Glu203Lys
c.607G>A

Protein change:

E122K

Links:

UniProtKB: P02545#VAR_039767; dbSNP: rs61195471

NCBI 1000 Genomes Browser:

rs61195471

Molecular consequence:

NM_001257374.3:c.271G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.364G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.607G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.607G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.607G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.607G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.607G>A - 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
SCV000065048	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Feb 20, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11561226, 18606848, 20160190, 18585512, 23427149, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000065048

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Feb 20, 2018)

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	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease.

Jakobs PM, Hanson EL, Crispell KA, Toy W, Keegan H, Schilling K, Icenogle TB, Litt M, Hershberger RE.

J Card Fail. 2001 Sep;7(3):249-56.

PubMed [citation]

PMID:: 11561226

Sumoylation regulates lamin A function and is lost in lamin A mutants associated with familial cardiomyopathies.

Zhang YQ, Sarge KD.

J Cell Biol. 2008 Jul 14;182(1):35-9. doi: 10.1083/jcb.200712124. Epub 2008 Jul 7.

PubMed [citation]

PMID:: 18606848
PMCID:: PMC2447889

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000065048.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Glu203Lys variant in LMNA has been reported in 2 individuals with dilated cardiomyopathy, and in one family segregated with DCM in two individuals and con duction system disease in another 6 individuals (Jakobs 2001, LMM data). It was also absent from large population studies. This variant has been reported in Cli nVar (Variation ID: 48070). In vitro functional studies provide some evidence th at the p.Glu203Lys variant may impact protein function (Cowan 2010), while anoth er had inconclusive findings (Zwerger 2013). However, these types of assays may not accurately represent biological function. Finally, another missense variant at this position has been reported to segregate with DCM (p.Glu203Gly; Fatkin 19 99). In summary, although additional studies are required to fully establish its clinical significance, the p.Glu203Lys variant is likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_ Strong, PM2, PS3_Supporting, PS4_Supporting.

#	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		2	not provided	2	not provided

Last Updated: Oct 8, 2024

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