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NM_170707.4(LMNA):c.497G>C (p.Arg166Pro) AND Primary dilated cardiomyopathy

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 30, 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:
RCV003993783.1

Allele description [Variation Report for NM_170707.4(LMNA):c.497G>C (p.Arg166Pro)]

NM_170707.4(LMNA):c.497G>C (p.Arg166Pro)

Genes:
LOC126805877:MED14-independent group 3 enhancer GRCh37_chr1:156099693-156100892 [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.497G>C (p.Arg166Pro)
Other names:
p.R166P:CGG>CCG
HGVS:
  • NC_000001.11:g.156130757G>C
  • NG_008692.2:g.53185G>C
  • NM_001257374.3:c.161G>C
  • NM_001282624.2:c.254G>C
  • NM_001282625.2:c.497G>C
  • NM_001282626.2:c.497G>C
  • NM_005572.4:c.497G>C
  • NM_170707.4:c.497G>CMANE SELECT
  • NM_170708.4:c.497G>C
  • NP_001244303.1:p.Arg54Pro
  • NP_001269553.1:p.Arg85Pro
  • NP_001269553.1:p.Arg85Pro
  • NP_001269554.1:p.Arg166Pro
  • NP_001269555.1:p.Arg166Pro
  • NP_005563.1:p.Arg166Pro
  • NP_733821.1:p.Arg166Pro
  • NP_733822.1:p.Arg166Pro
  • LRG_254t2:c.497G>C
  • LRG_254:g.53185G>C
  • NC_000001.10:g.156100548G>C
  • NM_001282624.1:c.254G>C
  • NM_170707.2:c.497G>C
  • NM_170707.3:c.497G>C
  • P02545:p.Arg166Pro
Protein change:
R166P
Links:
UniProtKB: P02545#VAR_070176; dbSNP: rs267607570
NCBI 1000 Genomes Browser:
rs267607570
Molecular consequence:
  • NM_001257374.3:c.161G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282624.2:c.254G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282625.2:c.497G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.497G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.497G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.497G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.497G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004812377Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Mar 30, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy.

Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Peterson A, Li D, Jakobs P, Litt M, Porter CB, Rahko PS, Hershberger RE.

Am Heart J. 2008 Jul;156(1):161-9. doi: 10.1016/j.ahj.2008.01.026. Epub 2008 Mar 12.

PubMed [citation]
PMID:
18585512
PMCID:
PMC2527054

Lamin A/C gene mutations in familial cardiomyopathy with advanced atrioventricular block and arrhythmia.

Saga A, Karibe A, Otomo J, Iwabuchi K, Takahashi T, Kanno H, Kikuchi J, Keitoku M, Shinozaki T, Shimokawa H.

Tohoku J Exp Med. 2009 Aug;218(4):309-16.

PubMed [citation]
PMID:
19638735
See all PubMed Citations (7)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812377.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change in LMNA is predicted to replace arginine with proline at codon 166, p.(Arg166Pro). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the coil 1B domain. There is a large physicochemical difference between arginine and proline. This variant is present in a single Europrean (non-Finnish) individual from the population database gnomAD v3.1. This variant has been reported in at least four probands with a phenotype suggestive of LMNA-related cardiomyopathy which includes dilated cardiomyopathy and arrhythmia and/or conduction system disease (PMID: 18585512, 19638735, 30739589). The variant has been reported to segregate with cardiomyopathy in affected family members from one family (PMID: 33029862). Nuclear aggregation assays in cell lines showed increased aggregation indicating that this variant impacts protein function (PMID: 20160190, 34862408). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4, PS3_Moderate, PM2_Supporting, PP1, PP3.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024