NM_170707.4(LMNA):c.565C>T (p.Arg189Trp) AND Primary dilated cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 2, 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:: RCV000148603.4

Allele description [Variation Report for NM_170707.4(LMNA):c.565C>T (p.Arg189Trp)]

NM_170707.4(LMNA):c.565C>T (p.Arg189Trp)

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.565C>T (p.Arg189Trp)

HGVS:

NC_000001.11:g.156134454C>T
NG_008692.2:g.56882C>T
NM_001257374.3:c.229C>T
NM_001282624.2:c.322C>T
NM_001282625.2:c.565C>T
NM_001282626.2:c.565C>T
NM_005572.4:c.565C>T
NM_170707.4:c.565C>TMANE SELECT
NM_170708.4:c.565C>T
NP_001244303.1:p.Arg77Trp
NP_001269553.1:p.Arg108Trp
NP_001269554.1:p.Arg189Trp
NP_001269555.1:p.Arg189Trp
NP_005563.1:p.Arg189Trp
NP_733821.1:p.Arg189Trp
NP_733822.1:p.Arg189Trp
LRG_254t2:c.565C>T
LRG_254:g.56882C>T
NC_000001.10:g.156104245C>T
NM_001257374.1:c.229C>T
NM_170707.2:c.565C>T
NM_170707.3:c.565C>T

Protein change:

R108W

Links:

dbSNP: rs267607626

NCBI 1000 Genomes Browser:

rs267607626

Molecular consequence:

NM_001257374.3:c.229C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.565C>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
SCV000190318	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV004834644	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 2, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20307303, 22326558, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190318

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV004834644

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 2, 2023)

germline

clinical testing

PubMed (3)
[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, research

Citations

PubMed

A novel LMNA mutation (R189W) in familial dilated cardiomyopathy: evidence for a 'hot spot' region at exon 3: a case report.

Botto N, Vittorini S, Colombo MG, Biagini A, Paradossi U, Aquaro G, Andreassi MG.

Cardiovasc Ultrasound. 2010 Mar 22;8:9. doi: 10.1186/1476-7120-8-9.

PubMed [citation]

PMID:: 20307303
PMCID:: PMC2859370

Protein profiling reveals energy metabolism and cytoskeletal protein alterations in LMNA mutation carriers.

Magagnotti C, Bachi A, Zerbini G, Fattore E, Fermo I, Riba M, Previtali SC, Ferrari M, Andolfo A, Benedetti S.

Biochim Biophys Acta. 2012 Jun;1822(6):970-9. doi: 10.1016/j.bbadis.2012.01.014. Epub 2012 Feb 3.

PubMed [citation]

PMID:: 22326558

See all PubMed Citations (3)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190318.1

#	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 All of Us Research Program, National Institutes of Health, SCV004834644.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with tryptophan at codon 189 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy, cardiac conduction abnormalities and a strong family history of sudden cardiac death (PMID: 20307303). This variant has been reported in an individual with dilated cardiomyopathy, limb-girdle muscular dystrophy and peripheral neuropathy (PMID: 22326558). This variant has been identified in 5/282762 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 7, 2024

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