NM_170707.4(LMNA):c.1162C>T (p.Arg388Cys) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 12, 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:: RCV001854173.6

Allele description [Variation Report for NM_170707.4(LMNA):c.1162C>T (p.Arg388Cys)]

NM_170707.4(LMNA):c.1162C>T (p.Arg388Cys)

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.1162C>T (p.Arg388Cys)

HGVS:

NC_000001.11:g.156136218C>T
NG_008692.2:g.58646C>T
NM_001257374.3:c.826C>T
NM_001282624.2:c.919C>T
NM_001282625.2:c.1162C>T
NM_001282626.2:c.1162C>T
NM_005572.4:c.1162C>T
NM_170707.4:c.1162C>TMANE SELECT
NM_170708.4:c.1162C>T
NP_001244303.1:p.Arg276Cys
NP_001269553.1:p.Arg307Cys
NP_001269554.1:p.Arg388Cys
NP_001269555.1:p.Arg388Cys
NP_005563.1:p.Arg388Cys
NP_733821.1:p.Arg388Cys
NP_733822.1:p.Arg388Cys
LRG_254t2:c.1162C>T
LRG_254:g.58646C>T
NC_000001.10:g.156106009C>T
NM_170707.2:c.1162C>T

Protein change:

R276C

Links:

dbSNP: rs58133342

NCBI 1000 Genomes Browser:

rs58133342

Molecular consequence:

NM_001257374.3:c.826C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.919C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1162C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1162C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1162C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1162C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1162C>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
SCV002239142	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 12, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28125586, 17377071, 32528171, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002239142

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 12, 2023)

germline

clinical testing

PubMed (4)
[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

A Novel Lamin A Mutant Responsible for Congenital Muscular Dystrophy Causes Distinct Abnormalities of the Cell Nucleus.

Barateau A, Vadrot N, Vicart P, Ferreiro A, Mayer M, Héron D, Vigouroux C, Buendia B.

PLoS One. 2017;12(1):e0169189. doi: 10.1371/journal.pone.0169189.

PubMed [citation]

PMID:: 28125586
PMCID:: PMC5268432

Phenotypic clustering of lamin A/C mutations in neuromuscular patients.

Benedetti S, Menditto I, Degano M, Rodolico C, Merlini L, D'Amico A, Palmucci L, Berardinelli A, Pegoraro E, Trevisan CP, Morandi L, Moroni I, Galluzzi G, Bertini E, Toscano A, Olivè M, Bonne G, Mari F, Caldara R, Fazio R, Mammì I, Carrera P, et al.

Neurology. 2007 Sep 18;69(12):1285-92. Epub 2007 Mar 21.

PubMed [citation]

PMID:: 17377071

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002239142.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. This variant disrupts the p.Arg388 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28125586). 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. ClinVar contains an entry for this variant (Variation ID: 66789). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 17377071, 32528171). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 388 of the LMNA protein (p.Arg388Cys).

#	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: Sep 29, 2024

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