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NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 5, 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:
RCV004639121.1

Allele description [Variation Report for NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp)]

NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp)

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.1357C>T (p.Arg453Trp)
HGVS:
  • NC_000001.11:g.156136413C>T
  • NG_008692.2:g.58841C>T
  • NM_001257374.3:c.1021C>T
  • NM_001282624.2:c.1114C>T
  • NM_001282625.2:c.1357C>T
  • NM_001282626.2:c.1357C>T
  • NM_005572.4:c.1357C>T
  • NM_170707.4:c.1357C>TMANE SELECT
  • NM_170708.4:c.1357C>T
  • NP_001244303.1:p.Arg341Trp
  • NP_001269553.1:p.Arg372Trp
  • NP_001269554.1:p.Arg453Trp
  • NP_001269555.1:p.Arg453Trp
  • NP_005563.1:p.Arg453Trp
  • NP_733821.1:p.Arg453Trp
  • NP_733822.1:p.Arg453Trp
  • LRG_254t2:c.1357C>T
  • LRG_254:g.58841C>T
  • NC_000001.10:g.156106204C>T
  • NM_005572.4:c.1357C>T
  • NM_170707.2:c.1357C>T
  • NM_170707.3:c.1357C>T
  • P02545:p.Arg453Trp
Protein change:
R341W; ARG453TRP
Links:
UniProtKB: P02545#VAR_009988; OMIM: 150330.0002; dbSNP: rs58932704
NCBI 1000 Genomes Browser:
rs58932704
Molecular consequence:
  • NM_001257374.3:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282624.2:c.1114C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282625.2:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functionally_abnormal [Sequence Ontology: SO:0002218]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005130629Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Apr 5, 2024) 		germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.

Bonne G, Di Barletta MR, Varnous S, Bécane HM, Hammouda EH, Merlini L, Muntoni F, Greenberg CR, Gary F, Urtizberea JA, Duboc D, Fardeau M, Toniolo D, Schwartz K.

Nat Genet. 1999 Mar;21(3):285-8.

PubMed [citation]
PMID:
10080180

Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy.

Raffaele Di Barletta M, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L, Romorini A, Voit T, Orstavik KH, Merlini L, Trevisan C, Biancalana V, Housmanowa-Petrusewicz I, Bione S, Ricotti R, Schwartz K, Bonne G, Toniolo D.

Am J Hum Genet. 2000 Apr;66(4):1407-12. Epub 2000 Mar 16.

PubMed [citation]
PMID:
10739764
PMCID:
PMC1288205
See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV005130629.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

The p.R453W pathogenic mutation (also known as c.1357C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1357. The arginine at codon 453 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in multiple individuals with features consistent with laminopathies, most commonly Emery-Dreifuss muscular dystrophy with or without cardiac manifestations, has been reported to occur de novo in affected cases, and has also shown segregation with disease features in families (Bonne G et al. Nat Genet, 1999 Mar;21:285-8; Raffaele Di Barletta M et al. Am J Hum Genet, 2000 Apr;66:1407-12; Brown CA et al. Am J Med Genet, 2001 Sep;102:359-67; Favreau C et al. Mol Cell Biol, 2004 Feb;24:1481-92; Mitsuhashi H et al. J Cell Sci, 2010 Nov;123:3893-900; Scharner J et al. Hum Mutat, 2011 Feb;32:152-67; Magagnotti C et al. Biochim Biophys Acta, 2012 Jun;1822:970-9; Park HJ et al. Clin Genet, 2017 Mar;91:403-410; Wang L et al. Orphanet J Rare Dis, 2018 Aug;13:133; Westra D et al. J Neuromuscul Dis, 2019;6:241-258; Eldin AJ et al. Clin Endocrinol (Oxf), 2021 Jun;94:1043-1053; Iskandar K et al. BMC Pediatr, 2022 Oct;22:601). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

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

Last Updated: Nov 24, 2024