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NM_170707.4(LMNA):c.568C>T (p.Arg190Trp) AND Primary dilated cardiomyopathy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 12, 2024
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:
RCV003996512.2

Allele description [Variation Report for NM_170707.4(LMNA):c.568C>T (p.Arg190Trp)]

NM_170707.4(LMNA):c.568C>T (p.Arg190Trp)

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.568C>T (p.Arg190Trp)
Other names:
p.R190W:CGG>TGG
HGVS:
  • NC_000001.11:g.156134457C>T
  • NG_008692.2:g.56885C>T
  • NM_001257374.3:c.232C>T
  • NM_001282624.2:c.325C>T
  • NM_001282625.2:c.568C>T
  • NM_001282626.2:c.568C>T
  • NM_005572.4:c.568C>T
  • NM_170707.4:c.568C>TMANE SELECT
  • NM_170708.4:c.568C>T
  • NP_001244303.1:p.Arg78Trp
  • NP_001269553.1:p.Arg109Trp
  • NP_001269553.1:p.Arg109Trp
  • NP_001269554.1:p.Arg190Trp
  • NP_001269555.1:p.Arg190Trp
  • NP_005563.1:p.Arg190Trp
  • NP_733821.1:p.Arg190Trp
  • NP_733822.1:p.Arg190Trp
  • LRG_254t2:c.568C>T
  • LRG_254:g.56885C>T
  • NC_000001.10:g.156104248C>T
  • NM_001282624.1:c.325C>T
  • NM_170707.2:c.568C>T
  • NM_170707.3:c.568C>T
  • P02545:p.Arg190Trp
Protein change:
R109W
Links:
UniProtKB: P02545#VAR_039764; dbSNP: rs59026483
NCBI 1000 Genomes Browser:
rs59026483
Molecular consequence:
  • NM_001257374.3:c.232C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282624.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282625.2:c.568C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.568C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.568C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.568C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.568C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004845015All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 12, 2024) 		germlineclinical testing

PubMed (16)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot provided108544not providedclinical testing

Citations

PubMed

Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease.

Arbustini E, Pilotto A, Repetto A, Grasso M, Negri A, Diegoli M, Campana C, Scelsi L, Baldini E, Gavazzi A, Tavazzi L.

J Am Coll Cardiol. 2002 Mar 20;39(6):981-90.

PubMed [citation]
PMID:
11897440

Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations.

Hermida-Prieto M, Monserrat L, Castro-Beiras A, Laredo R, Soler R, Peteiro J, Rodríguez E, Bouzas B, Alvarez N, Muñiz J, Crespo-Leiro M.

Am J Cardiol. 2004 Jul 1;94(1):50-4.

PubMed [citation]
PMID:
15219508
See all PubMed Citations (16)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004845015.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (16)

Description

This missense variant replaces arginine with tryptophan at codon 190 of the intermediate filament rod domain of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant may disrupt the viscoelasticity of lamin A in the nuclear envelope (PMID: 23701190, 24386194). This variant has been reported in more than 10 unrelated individuals affected with dilated cardiomyopathy (PMID: 11897440, 15219508, 15539782, 16061563, 16537768, 17334235, 29947763, 23349452, 26199943, 26899768, 29947763, 32041989, 32880476; DOI 10.3390 Cuesta-Llavona 2022). It has also been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 22199124). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 11897440, 15219508, 15539782, 16061563, 17334235, 29947763, 26199943). A different variant occurring at the same codon, p.Arg190Gln, is a well documented pathogenic mutation (Clinvar variation ID: 66910), indicating that arginine at this position is important for LMNA protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided2not providednot providednot provided

Last Updated: Jun 9, 2024