NM_170707.4(LMNA):c.1394G>A (p.Gly465Asp) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 29, 2022
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:: RCV001851878.5

Allele description [Variation Report for NM_170707.4(LMNA):c.1394G>A (p.Gly465Asp)]

NM_170707.4(LMNA):c.1394G>A (p.Gly465Asp)

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.1394G>A (p.Gly465Asp)

HGVS:

NC_000001.11:g.156136934G>A
NG_008692.2:g.59362G>A
NM_001257374.3:c.1058G>A
NM_001282624.2:c.1151G>A
NM_001282625.2:c.1394G>A
NM_001282626.2:c.1394G>A
NM_005572.4:c.1394G>A
NM_170707.4:c.1394G>AMANE SELECT
NM_170708.4:c.1394G>A
NP_001244303.1:p.Gly353Asp
NP_001269553.1:p.Gly384Asp
NP_001269554.1:p.Gly465Asp
NP_001269555.1:p.Gly465Asp
NP_005563.1:p.Gly465Asp
NP_005563.1:p.Gly465Asp
NP_733821.1:p.Gly465Asp
NP_733822.1:p.Gly465Asp
LRG_254t1:c.1394G>A
LRG_254t2:c.1394G>A
LRG_254:g.59362G>A
LRG_254p1:p.Gly465Asp
NC_000001.10:g.156106725G>A
NM_005572.3:c.1394G>A
NM_170707.2:c.1394G>A
P02545:p.Gly465Asp

Protein change:

G353D; GLY465ASP

Links:

UniProtKB: P02545#VAR_009989; OMIM: 150330.0015; dbSNP: rs61282106

NCBI 1000 Genomes Browser:

rs61282106

Molecular consequence:

NM_001257374.3:c.1058G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1151G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1394G>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
SCV002292075	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12729796, 23243001, 25982065, 10739751, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002292075

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (5)
[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

Effects of expressing lamin A mutant protein causing Emery-Dreifuss muscular dystrophy and familial partial lipodystrophy in HeLa cells.

Bechert K, Lagos-Quintana M, Harborth J, Weber K, Osborn M.

Exp Cell Res. 2003 May 15;286(1):75-86.

PubMed [citation]

PMID:: 12729796

Lamin A tail modification by SUMO1 is disrupted by familial partial lipodystrophy-causing mutations.

Simon DN, Domaradzki T, Hofmann WA, Wilson KL.

Mol Biol Cell. 2013 Feb;24(3):342-50. doi: 10.1091/mbc.E12-07-0527. Epub 2012 Dec 14.

PubMed [citation]

PMID:: 23243001
PMCID:: PMC3564541

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002292075.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. Experimental studies have shown that this missense change affects LMNA function (PMID: 12729796, 23243001, 25982065). 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: 14493). This missense change has been observed in individual(s) with autosomal dominant familial partial lipodystrophy (PMID: 10739751). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 465 of the LMNA protein (p.Gly465Asp).

#	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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