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NM_170707.4(LMNA):c.1046G>A (p.Arg349Gln) AND Charcot-Marie-Tooth disease type 2

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 27, 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:
RCV003743173.2

Allele description [Variation Report for NM_170707.4(LMNA):c.1046G>A (p.Arg349Gln)]

NM_170707.4(LMNA):c.1046G>A (p.Arg349Gln)

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.1046G>A (p.Arg349Gln)
HGVS:
  • NC_000001.11:g.156136010G>A
  • NG_008692.2:g.58438G>A
  • NM_001257374.3:c.710G>A
  • NM_001282624.2:c.803G>A
  • NM_001282625.2:c.1046G>A
  • NM_001282626.2:c.1046G>A
  • NM_001406983.1:c.1046G>A
  • NM_001406984.1:c.1046G>A
  • NM_001406985.1:c.1046G>A
  • NM_001406986.1:c.803G>A
  • NM_001406987.1:c.803G>A
  • NM_001406988.1:c.749G>A
  • NM_001406989.1:c.710G>A
  • NM_001406990.1:c.488G>A
  • NM_001406991.1:c.1046G>A
  • NM_001406992.1:c.1046G>A
  • NM_001406993.1:c.488G>A
  • NM_001406994.1:c.422G>A
  • NM_001406995.1:c.488G>A
  • NM_001406996.1:c.488G>A
  • NM_001406997.1:c.488G>A
  • NM_001406998.1:c.710G>A
  • NM_001406999.1:c.422G>A
  • NM_001407000.1:c.422G>A
  • NM_001407001.1:c.422G>A
  • NM_001407002.1:c.488G>A
  • NM_001407003.1:c.488G>A
  • NM_005572.4:c.1046G>A
  • NM_170707.4:c.1046G>AMANE SELECT
  • NM_170708.4:c.1046G>A
  • NP_001244303.1:p.Arg237Gln
  • NP_001269553.1:p.Arg268Gln
  • NP_001269554.1:p.Arg349Gln
  • NP_001269555.1:p.Arg349Gln
  • NP_001393912.1:p.Arg349Gln
  • NP_001393913.1:p.Arg349Gln
  • NP_001393914.1:p.Arg349Gln
  • NP_001393915.1:p.Arg268Gln
  • NP_001393916.1:p.Arg268Gln
  • NP_001393917.1:p.Arg250Gln
  • NP_001393918.1:p.Arg237Gln
  • NP_001393919.1:p.Arg163Gln
  • NP_001393920.1:p.Arg349Gln
  • NP_001393921.1:p.Arg349Gln
  • NP_001393922.1:p.Arg163Gln
  • NP_001393923.1:p.Arg141Gln
  • NP_001393924.1:p.Arg163Gln
  • NP_001393925.1:p.Arg163Gln
  • NP_001393926.1:p.Arg163Gln
  • NP_001393927.1:p.Arg237Gln
  • NP_001393928.1:p.Arg141Gln
  • NP_001393929.1:p.Arg141Gln
  • NP_001393930.1:p.Arg141Gln
  • NP_001393931.1:p.Arg163Gln
  • NP_001393932.1:p.Arg163Gln
  • NP_005563.1:p.Arg349Gln
  • NP_005563.1:p.Arg349Gln
  • NP_733821.1:p.Arg349Gln
  • NP_733821.1:p.Arg349Gln
  • NP_733822.1:p.Arg349Gln
  • NP_733822.1:p.Arg349Gln
  • LRG_254t1:c.1046G>A
  • LRG_254t2:c.1046G>A
  • LRG_254t3:c.1046G>A
  • LRG_254:g.58438G>A
  • LRG_254p1:p.Arg349Gln
  • LRG_254p2:p.Arg349Gln
  • LRG_254p3:p.Arg349Gln
  • NC_000001.10:g.156105801G>A
  • NM_005572.3:c.1046G>A
  • NM_170707.2:c.1046G>A
  • NM_170708.2:c.1046G>A
  • NR_047544.1:n.1687G>A
  • NR_047545.1:n.934G>A
Protein change:
R141Q
Molecular consequence:
  • NM_001257374.3:c.710G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282624.2:c.803G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282625.2:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406983.1:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406984.1:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406985.1:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406986.1:c.803G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406987.1:c.803G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406988.1:c.749G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406989.1:c.710G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406990.1:c.488G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406991.1:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406992.1:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406993.1:c.488G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406994.1:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406995.1:c.488G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406996.1:c.488G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406997.1:c.488G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406998.1:c.710G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406999.1:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407000.1:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407001.1:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407002.1:c.488G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407003.1:c.488G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.1046G>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
SCV004462311Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(May 27, 2023) 		germlineclinical testing

PubMed (8)
[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

High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics.

van Tintelen JP, Hofstra RM, Katerberg H, Rossenbacker T, Wiesfeld AC, du Marchie Sarvaas GJ, Wilde AA, van Langen IM, Nannenberg EA, van der Kooi AJ, Kraak M, van Gelder IC, van Veldhuisen DJ, Vos Y, van den Berg MP; Working Group on Inherited Cardiac Disorders, line 27/50, Interuniversity Cardiology Institute of The Netherlands..

Am Heart J. 2007 Dec;154(6):1130-9. Epub 2007 Sep 14.

PubMed [citation]
PMID:
18035086

Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations.

Mory PB, Crispim F, Freire MB, Salles JE, Valério CM, Godoy-Matos AF, Dib SA, Moisés RS.

Eur J Endocrinol. 2012 Sep;167(3):423-31. doi: 10.1530/EJE-12-0268. Epub 2012 Jun 14.

PubMed [citation]
PMID:
22700598
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004462311.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This variant disrupts the p.Arg349 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18035086, 22700598, 24080738, 28620495, 28641778). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546, 27532257). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 349 of the LMNA protein (p.Arg349Gln). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Sep 29, 2024