NM_170707.4(LMNA):c.565C>T (p.Arg189Trp) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 21, 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:: RCV000794744.9

Allele description [Variation Report for NM_170707.4(LMNA):c.565C>T (p.Arg189Trp)]

NM_170707.4(LMNA):c.565C>T (p.Arg189Trp)

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.565C>T (p.Arg189Trp)

HGVS:

NC_000001.11:g.156134454C>T
NG_008692.2:g.56882C>T
NM_001257374.3:c.229C>T
NM_001282624.2:c.322C>T
NM_001282625.2:c.565C>T
NM_001282626.2:c.565C>T
NM_005572.4:c.565C>T
NM_170707.4:c.565C>TMANE SELECT
NM_170708.4:c.565C>T
NP_001244303.1:p.Arg77Trp
NP_001269553.1:p.Arg108Trp
NP_001269554.1:p.Arg189Trp
NP_001269555.1:p.Arg189Trp
NP_005563.1:p.Arg189Trp
NP_733821.1:p.Arg189Trp
NP_733822.1:p.Arg189Trp
LRG_254t2:c.565C>T
LRG_254:g.56882C>T
NC_000001.10:g.156104245C>T
NM_001257374.1:c.229C>T
NM_170707.2:c.565C>T
NM_170707.3:c.565C>T

Protein change:

R108W

Links:

dbSNP: rs267607626

NCBI 1000 Genomes Browser:

rs267607626

Molecular consequence:

NM_001257374.3:c.229C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.565C>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
SCV000934170	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20307303, 22326558, 33963534, 34768595, 20848652, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000934170

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 21, 2023)

germline

clinical testing

PubMed (6)
[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 LMNA mutation (R189W) in familial dilated cardiomyopathy: evidence for a 'hot spot' region at exon 3: a case report.

Botto N, Vittorini S, Colombo MG, Biagini A, Paradossi U, Aquaro G, Andreassi MG.

Cardiovasc Ultrasound. 2010 Mar 22;8:9. doi: 10.1186/1476-7120-8-9.

PubMed [citation]

PMID:: 20307303
PMCID:: PMC2859370

Protein profiling reveals energy metabolism and cytoskeletal protein alterations in LMNA mutation carriers.

Magagnotti C, Bachi A, Zerbini G, Fattore E, Fermo I, Riba M, Previtali SC, Ferrari M, Andolfo A, Benedetti S.

Biochim Biophys Acta. 2012 Jun;1822(6):970-9. doi: 10.1016/j.bbadis.2012.01.014. Epub 2012 Feb 3.

PubMed [citation]

PMID:: 22326558

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000934170.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 189 of the LMNA protein (p.Arg189Trp). This variant is present in population databases (rs267607626, gnomAD 0.005%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or limb-girdle muscular dystrophy (PMID: 20307303, 22326558, 33963534, 34768595). This variant is also known as c.229C>T; p.Arg77Trp. ClinVar contains an entry for this variant (Variation ID: 66906). 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%. This variant disrupts the p.Arg189 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 20848652), which suggests that this may be a clinically significant amino acid residue. 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: Sep 29, 2024

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