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NM_170707.4(LMNA):c.121C>T (p.Arg41Cys) AND Charcot-Marie-Tooth disease type 2

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 18, 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:
RCV003581422.2

Allele description [Variation Report for NM_170707.4(LMNA):c.121C>T (p.Arg41Cys)]

NM_170707.4(LMNA):c.121C>T (p.Arg41Cys)

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.121C>T (p.Arg41Cys)
HGVS:
  • NC_000001.11:g.156115039C>T
  • NG_008692.2:g.37467C>T
  • NG_164640.1:g.206C>T
  • NM_001282625.2:c.121C>T
  • NM_001282626.2:c.121C>T
  • NM_001406983.1:c.121C>T
  • NM_001406984.1:c.121C>T
  • NM_001406985.1:c.121C>T
  • NM_001406986.1:c.-303C>T
  • NM_001406990.1:c.-281C>T
  • NM_001406991.1:c.121C>T
  • NM_001406992.1:c.121C>T
  • NM_001406993.1:c.-203+8216C>T
  • NM_001406994.1:c.-544C>T
  • NM_001406995.1:c.-281C>T
  • NM_001406999.1:c.-724C>T
  • NM_001407000.1:c.-544C>T
  • NM_001407001.1:c.-387C>T
  • NM_001407002.1:c.-281C>T
  • NM_001407003.1:c.-203+8216C>T
  • NM_005572.4:c.121C>T
  • NM_170707.4:c.121C>TMANE SELECT
  • NM_170708.4:c.121C>T
  • NP_001269554.1:p.Arg41Cys
  • NP_001269555.1:p.Arg41Cys
  • NP_001393912.1:p.Arg41Cys
  • NP_001393913.1:p.Arg41Cys
  • NP_001393914.1:p.Arg41Cys
  • NP_001393920.1:p.Arg41Cys
  • NP_001393921.1:p.Arg41Cys
  • NP_005563.1:p.Arg41Cys
  • NP_005563.1:p.Arg41Cys
  • NP_733821.1:p.Arg41Cys
  • NP_733821.1:p.Arg41Cys
  • NP_733822.1:p.Arg41Cys
  • NP_733822.1:p.Arg41Cys
  • LRG_254t1:c.121C>T
  • LRG_254t2:c.121C>T
  • LRG_254t3:c.121C>T
  • LRG_254:g.37467C>T
  • LRG_254p1:p.Arg41Cys
  • LRG_254p2:p.Arg41Cys
  • LRG_254p3:p.Arg41Cys
  • NC_000001.10:g.156084830C>T
  • NM_005572.3:c.121C>T
  • NM_170707.2:c.121C>T
  • NM_170708.2:c.121C>T
  • NR_047544.1:n.762C>T
Protein change:
R41C
Molecular consequence:
  • NM_001406986.1:c.-303C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001406990.1:c.-281C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001406994.1:c.-544C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001406995.1:c.-281C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001406999.1:c.-724C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001407000.1:c.-544C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001407001.1:c.-387C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001407002.1:c.-281C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001406993.1:c.-203+8216C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407003.1:c.-203+8216C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001282625.2:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406983.1:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406984.1:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406985.1:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406991.1:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406992.1:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.121C>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
SCV004292900Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 18, 2024) 		germlineclinical testing

PubMed (4)
[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

Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance.

Anderson CL, Langer ER, Routes TC, McWilliams SF, Bereslavskyy I, Kamp TJ, Eckhardt LL.

NPJ Genom Med. 2021 Dec 3;6(1):103. doi: 10.1038/s41525-021-00265-x.

PubMed [citation]
PMID:
34862408
PMCID:
PMC8642518

Specific phosphorylation of Ser458 of A-type lamins in LMNA-associated myopathy patients.

Mitsuhashi H, Hayashi YK, Matsuda C, Noguchi S, Wakatsuki S, Araki T, Nishino I.

J Cell Sci. 2010 Nov 15;123(Pt 22):3893-900. doi: 10.1242/jcs.072157. Epub 2010 Oct 27.

PubMed [citation]
PMID:
20980393
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004292900.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 41 of the LMNA protein (p.Arg41Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with LMNA-related conditions (PMID: 20980393; Invitae). 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%. Experimental studies have shown that this missense change affects LMNA function (PMID: 34862408). This variant disrupts the p.Arg41 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20980393, 29250285). 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