NM_170707.4(LMNA):c.1027C>T (p.Arg343Trp) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 19, 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:: RCV000812997.6

Allele description [Variation Report for NM_170707.4(LMNA):c.1027C>T (p.Arg343Trp)]

NM_170707.4(LMNA):c.1027C>T (p.Arg343Trp)

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.1027C>T (p.Arg343Trp)

HGVS:

NC_000001.11:g.156135991C>T
NG_008692.2:g.58419C>T
NM_001257374.3:c.691C>T
NM_001282624.2:c.784C>T
NM_001282625.2:c.1027C>T
NM_001282626.2:c.1027C>T
NM_005572.4:c.1027C>T
NM_170707.4:c.1027C>TMANE SELECT
NM_170708.4:c.1027C>T
NP_001244303.1:p.Arg231Trp
NP_001269553.1:p.Arg262Trp
NP_001269554.1:p.Arg343Trp
NP_001269555.1:p.Arg343Trp
NP_005563.1:p.Arg343Trp
NP_005563.1:p.Arg343Trp
NP_733821.1:p.Arg343Trp
NP_733822.1:p.Arg343Trp
LRG_254t1:c.1027C>T
LRG_254t2:c.1027C>T
LRG_254:g.58419C>T
LRG_254p1:p.Arg343Trp
NC_000001.10:g.156105782C>T
NM_005572.3:c.1027C>T
NM_170707.2:c.1027C>T
NM_170707.3:c.1027C>T

Protein change:

R231W

Links:

dbSNP: rs749784223

NCBI 1000 Genomes Browser:

rs749784223

Molecular consequence:

NM_001257374.3:c.691C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.784C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1027C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000953329	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32376792, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000953329

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 19, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.

Volodarsky M, Kerkhof J, Stuart A, Levy M, Brady LI, Tarnopolsky M, Lin H, Ainsworth P, Sadikovic B.

J Med Genet. 2021 Apr;58(4):284-288. doi: 10.1136/jmedgenet-2019-106641. Epub 2020 May 6.

PubMed [citation]

PMID:: 32376792

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000953329.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 343 of the LMNA protein (p.Arg343Trp). This variant is present in population databases (rs749784223, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic cardiomyopathy and/or clinical features of Charcot-Marie-Tooth disease (PMID: 32376792; Invitae). ClinVar contains an entry for this variant (Variation ID: 656550). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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