NM_170707.4(LMNA):c.1081G>A (p.Glu361Lys) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 5, 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:: RCV001218431.9

Allele description [Variation Report for NM_170707.4(LMNA):c.1081G>A (p.Glu361Lys)]

NM_170707.4(LMNA):c.1081G>A (p.Glu361Lys)

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.1081G>A (p.Glu361Lys)

HGVS:

NC_000001.11:g.156136045G>A
NG_008692.2:g.58473G>A
NM_001257374.3:c.745G>A
NM_001282624.2:c.838G>A
NM_001282625.2:c.1081G>A
NM_001282626.2:c.1081G>A
NM_005572.4:c.1081G>A
NM_170707.4:c.1081G>AMANE SELECT
NM_170708.4:c.1081G>A
NP_001244303.1:p.Glu249Lys
NP_001269553.1:p.Glu280Lys
NP_001269554.1:p.Glu361Lys
NP_001269555.1:p.Glu361Lys
NP_005563.1:p.Glu361Lys
NP_733821.1:p.Glu361Lys
NP_733822.1:p.Glu361Lys
LRG_254t2:c.1081G>A
LRG_254:g.58473G>A
NC_000001.10:g.156105836G>A
NM_170707.2:c.1081G>A
NM_170707.3:c.1081G>A
P02545:p.Glu361Lys

Protein change:

E249K

Links:

UniProtKB: P02545#VAR_064970; dbSNP: rs267607634

NCBI 1000 Genomes Browser:

rs267607634

Molecular consequence:

NM_001257374.3:c.745G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.838G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1081G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1081G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1081G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1081G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1081G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001390313	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 5, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16218190, 20848652, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001390313

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 5, 2023)

germline

clinical testing

PubMed (3)
[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

Lamins A and C are differentially dysfunctional in autosomal dominant Emery-Dreifuss muscular dystrophy.

Motsch I, Kaluarachchi M, Emerson LJ, Brown CA, Brown SC, Dabauvalle MC, Ellis JA.

Eur J Cell Biol. 2005 Sep;84(9):765-81.

PubMed [citation]

PMID:: 16218190

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations.

Scharner J, Brown CA, Bower M, Iannaccone ST, Khatri IA, Escolar D, Gordon E, Felice K, Crowe CA, Grosmann C, Meriggioli MN, Asamoah A, Gordon O, Gnocchi VF, Ellis JA, Mendell JR, Zammit PS.

Hum Mutat. 2011 Feb;32(2):152-67. doi: 10.1002/humu.21361. Epub 2011 Jan 25.

PubMed [citation]

PMID:: 20848652

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001390313.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 16218190). 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: 66772). This missense change has been observed in individual(s) with clinical features of autosomal dominant Emery-Dreifuss muscular dystrophy (PMID: 20848652; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 361 of the LMNA protein (p.Glu361Lys).

#	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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