NM_170707.4(LMNA):c.1A>T (p.Met1Leu) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 30, 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:: RCV001390690.6

Allele description [Variation Report for NM_170707.4(LMNA):c.1A>T (p.Met1Leu)]

NM_170707.4(LMNA):c.1A>T (p.Met1Leu)

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.1A>T (p.Met1Leu)

HGVS:

NC_000001.11:g.156114919A>T
NG_008692.2:g.37347A>T
NM_001282625.2:c.1A>T
NM_001282626.2:c.1A>T
NM_005572.4:c.1A>T
NM_170707.4:c.1A>TMANE SELECT
NM_170708.4:c.1A>T
NP_001269554.1:p.Met1Leu
NP_001269555.1:p.Met1Leu
NP_005563.1:p.Met1Leu
NP_733821.1:p.Met1Leu
NP_733822.1:p.Met1Leu
LRG_254:g.37347A>T
NC_000001.10:g.156084710A>T

Protein change:

M1L

Links:

dbSNP: rs2102816719

NCBI 1000 Genomes Browser:

rs2102816719

Molecular consequence:

NM_001282625.2:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001282626.2:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_005572.4:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_170707.4:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_170708.4:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001282625.2:c.1A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1A>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
SCV001592491	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 30, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14684700, 20092787, 31296869, 26620845, 29211919, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001592491

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 30, 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

Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes.

Vytopil M, Benedetti S, Ricci E, Galluzzi G, Dello Russo A, Merlini L, Boriani G, Gallina M, Morandi L, Politano L, Moggio M, Chiveri L, Hausmanova-Petrusewicz I, Ricotti R, Vohanka S, Toman J, Toniolo D.

J Med Genet. 2003 Dec;40(12):e132. No abstract available.

PubMed [citation]

PMID:: 14684700
PMCID:: PMC1735334

R25G mutation in exon 1 of LMNA gene is associated with dilated cardiomyopathy and limb-girdle muscular dystrophy 1B.

Yuan WL, Huang CY, Wang JF, Xie SL, Nie RQ, Liu YM, Liu PM, Zhou SX, Chen SQ, Huang WJ.

Chin Med J (Engl). 2009 Dec 5;122(23):2840-5.

PubMed [citation]

PMID:: 20092787

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001592491.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg25 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14684700, 20092787, 31296869). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1076704). Disruption of the initiator codon has been observed in individuals with clinical features of LMNA-related conditions (PMID: 26620845, 29211919; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the LMNA mRNA. The next in-frame methionine is located at codon 187.

#	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: Mar 5, 2024

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