NM_170707.4(LMNA):c.134A>G (p.Tyr45Cys) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 4, 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:: RCV000692072.15

Allele description [Variation Report for NM_170707.4(LMNA):c.134A>G (p.Tyr45Cys)]

NM_170707.4(LMNA):c.134A>G (p.Tyr45Cys)

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.134A>G (p.Tyr45Cys)

HGVS:

NC_000001.11:g.156115052A>G
NG_008692.2:g.37480A>G
NM_001282625.2:c.134A>G
NM_001282626.2:c.134A>G
NM_005572.4:c.134A>G
NM_170707.4:c.134A>GMANE SELECT
NM_170708.4:c.134A>G
NP_001269554.1:p.Tyr45Cys
NP_001269555.1:p.Tyr45Cys
NP_005563.1:p.Tyr45Cys
NP_005563.1:p.Tyr45Cys
NP_733821.1:p.Tyr45Cys
NP_733822.1:p.Tyr45Cys
LRG_254t1:c.134A>G
LRG_254t2:c.134A>G
LRG_254:g.37480A>G
LRG_254p1:p.Tyr45Cys
NC_000001.10:g.156084843A>G
NM_005572.3:c.134A>G
NM_170707.2:c.134A>G
NM_170707.3:c.134A>G
P02545:p.Tyr45Cys

Protein change:

Y45C

Links:

UniProtKB: P02545#VAR_009971; dbSNP: rs58436778

NCBI 1000 Genomes Browser:

rs58436778

Molecular consequence:

NM_001282625.2:c.134A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.134A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.134A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.134A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.134A>G - 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
SCV000819879	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10939567, 20848652, 23183350, 31434876, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000819879

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2023)

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

Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.

Bonne G, Mercuri E, Muchir A, Urtizberea A, Bécane HM, Recan D, Merlini L, Wehnert M, Boor R, Reuner U, Vorgerd M, Wicklein EM, Eymard B, Duboc D, Penisson-Besnier I, Cuisset JM, Ferrer X, Desguerre I, Lacombe D, Bushby K, Pollitt C, Toniolo D, et al.

Ann Neurol. 2000 Aug;48(2):170-80.

PubMed [citation]

PMID:: 10939567

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 (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000819879.4

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 45 of the LMNA protein (p.Tyr45Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant laminopathies (PMID: 10939567, 20848652, 23183350; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66807). 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. Experimental studies have shown that this missense change affects LMNA function (PMID: 31434876). For these reasons, this variant has been classified as Pathogenic.

#	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: Nov 10, 2024

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