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NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys) AND Charcot-Marie-Tooth disease type 2

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 15, 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:
RCV000469099.10

Allele description [Variation Report for NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys)]

NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys)

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.1129C>T (p.Arg377Cys)
HGVS:
  • NC_000001.11:g.156136093C>T
  • NG_008692.2:g.58521C>T
  • NM_001257374.3:c.793C>T
  • NM_001282624.2:c.886C>T
  • NM_001282625.2:c.1129C>T
  • NM_001282626.2:c.1129C>T
  • NM_005572.4:c.1129C>T
  • NM_170707.4:c.1129C>TMANE SELECT
  • NM_170708.4:c.1129C>T
  • NP_001244303.1:p.Arg265Cys
  • NP_001269553.1:p.Arg296Cys
  • NP_001269554.1:p.Arg377Cys
  • NP_001269555.1:p.Arg377Cys
  • NP_005563.1:p.Arg377Cys
  • NP_005563.1:p.Arg377Cys
  • NP_733821.1:p.Arg377Cys
  • NP_733822.1:p.Arg377Cys
  • LRG_254t1:c.1129C>T
  • LRG_254t2:c.1129C>T
  • LRG_254:g.58521C>T
  • LRG_254p1:p.Arg377Cys
  • NC_000001.10:g.156105884C>T
  • NM_005572.3:c.1129C>T
  • NM_170707.2:c.1129C>T
  • NM_170707.3:c.1129C>T
  • c.1129C>T
  • p.(Arg377Cys)
Protein change:
R265C
Links:
dbSNP: rs397517889
NCBI 1000 Genomes Browser:
rs397517889
Molecular consequence:
  • NM_001257374.3:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282624.2:c.886C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282625.2:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth disease type 2
Synonyms:
Charcot-Marie-Tooth, Type 2
Identifiers:
MONDO: MONDO:0018993; MedGen: C0270914

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000548870Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 15, 2024) 		germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan.

Astejada MN, Goto K, Nagano A, Ura S, Noguchi S, Nonaka I, Nishino I, Hayashi YK.

Acta Myol. 2007 Dec;26(3):159-64. Review.

PubMed [citation]
PMID:
18646565
PMCID:
PMC2949309

Inflammatory changes in infantile-onset LMNA-associated myopathy.

Komaki H, Hayashi YK, Tsuburaya R, Sugie K, Kato M, Nagai T, Imataka G, Suzuki S, Saitoh S, Asahina N, Honke K, Higuchi Y, Sakuma H, Saito Y, Nakagawa E, Sugai K, Sasaki M, Nonaka I, Nishino I.

Neuromuscul Disord. 2011 Aug;21(8):563-8. doi: 10.1016/j.nmd.2011.04.010. Epub 2011 May 31.

PubMed [citation]
PMID:
21632249
See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000548870.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 377 of the LMNA protein (p.Arg377Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cardiomyopathy and muscular dystrophy (PMID: 18646565, 21632249, 21840938, 23183350, 24503780). ClinVar contains an entry for this variant (Variation ID: 48031). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg377 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12628721, 12673789, 15053843, 16386954). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024