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NM_170707.4(LMNA):c.1130G>A (p.Arg377His) AND Charcot-Marie-Tooth disease type 2

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 3, 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:
RCV000547164.10

Allele description [Variation Report for NM_170707.4(LMNA):c.1130G>A (p.Arg377His)]

NM_170707.4(LMNA):c.1130G>A (p.Arg377His)

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.1130G>A (p.Arg377His)
HGVS:
  • NC_000001.11:g.156136094G>A
  • NG_008692.2:g.58522G>A
  • NM_001257374.3:c.794G>A
  • NM_001282624.2:c.887G>A
  • NM_001282625.2:c.1130G>A
  • NM_001282626.2:c.1130G>A
  • NM_005572.4:c.1130G>A
  • NM_170707.4:c.1130G>AMANE SELECT
  • NM_170708.4:c.1130G>A
  • NP_001244303.1:p.Arg265His
  • NP_001269553.1:p.Arg296His
  • NP_001269554.1:p.Arg377His
  • NP_001269555.1:p.Arg377His
  • NP_005563.1:p.Arg377His
  • NP_733821.1:p.Arg377His
  • NP_733822.1:p.Arg377His
  • LRG_254t2:c.1130G>A
  • LRG_254t3:c.1130G>A
  • LRG_254:g.58522G>A
  • NC_000001.10:g.156105885G>A
  • NM_170707.2:c.1130G>A
  • NM_170707.3:c.1130G>A
  • NM_170708.2:c.1130G>A
  • P02545:p.Arg377His
Protein change:
R265H; ARG377HIS
Links:
UniProtKB: P02545#VAR_016205; OMIM: 150330.0017; dbSNP: rs61672878
NCBI 1000 Genomes Browser:
rs61672878
Molecular consequence:
  • NM_001257374.3:c.794G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282624.2:c.887G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282625.2:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.1130G>A - 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
SCV000657791Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 3, 2024) 		germlineclinical testing

PubMed (12)
[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

Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B).

Muchir A, Bonne G, van der Kooi AJ, van Meegen M, Baas F, Bolhuis PA, de Visser M, Schwartz K.

Hum Mol Genet. 2000 May 22;9(9):1453-9.

PubMed [citation]
PMID:
10814726

[Case with Emery-Dreifuss muscular dystrophy diagnosed forty-two years after onset and implanted with a cardiac resynchronization therapy defibrillator].

Sakiyama Y, Watanabe E, Otsuka M, Hirahara T, Momomura S, Hayashi Y.

Rinsho Shinkeigaku. 2014;54(6):489-94. Japanese.

PubMed [citation]
PMID:
24990833
See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000657791.8

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 377 of the LMNA protein (p.Arg377His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant limb-girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B) (PMID: 10814726, 12673789, 24990833, 26443318, 27220833). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14495). 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: 12673789, 19524666). 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: 18646565, 21632249, 21840938, 23183350, 24503780). 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