NM_170707.4(LMNA):c.3G>T (p.Met1Ile) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 15, 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:: RCV002515313.2

Allele description [Variation Report for NM_170707.4(LMNA):c.3G>T (p.Met1Ile)]

NM_170707.4(LMNA):c.3G>T (p.Met1Ile)

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.3G>T (p.Met1Ile)

Other names:

p.M1I:ATG>ATT

HGVS:

NC_000001.11:g.156114921G>T
NG_008692.2:g.37349G>T
NM_001282625.2:c.3G>T
NM_001282626.2:c.3G>T
NM_005572.4:c.3G>T
NM_170707.4:c.3G>TMANE SELECT
NM_170708.4:c.3G>T
NP_001269554.1:p.Met1Ile
NP_001269555.1:p.Met1Ile
NP_005563.1:p.Met1Ile
NP_733821.1:p.Met1Ile
NP_733822.1:p.Met1Ile
LRG_254t2:c.3G>T
LRG_254:g.37349G>T
NC_000001.10:g.156084712G>T
NM_170707.2:c.3G>T

Protein change:

M1I

Links:

dbSNP: rs794728598

NCBI 1000 Genomes Browser:

rs794728598

Molecular consequence:

NM_001282625.2:c.3G>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001282626.2:c.3G>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_005572.4:c.3G>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_170707.4:c.3G>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_170708.4:c.3G>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001282625.2:c.3G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.3G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.3G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.3G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.3G>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
SCV003459823	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 15, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17377071, 18551513, 20980393, 21632249, 29211919, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003459823

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 15, 2022)

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

Phenotypic clustering of lamin A/C mutations in neuromuscular patients.

Benedetti S, Menditto I, Degano M, Rodolico C, Merlini L, D'Amico A, Palmucci L, Berardinelli A, Pegoraro E, Trevisan CP, Morandi L, Moroni I, Galluzzi G, Bertini E, Toscano A, Olivè M, Bonne G, Mari F, Caldara R, Fazio R, Mammì I, Carrera P, et al.

Neurology. 2007 Sep 18;69(12):1285-92. Epub 2007 Mar 21.

PubMed [citation]

PMID:: 17377071

De novo LMNA mutations cause a new form of congenital muscular dystrophy.

Quijano-Roy S, Mbieleu B, Bönnemann CG, Jeannet PY, Colomer J, Clarke NF, Cuisset JM, Roper H, De Meirleir L, D'Amico A, Ben Yaou R, Nascimento A, Barois A, Demay L, Bertini E, Ferreiro A, Sewry CA, Romero NB, Ryan M, Muntoni F, Guicheney P, Richard P, et al.

Ann Neurol. 2008 Aug;64(2):177-86. doi: 10.1002/ana.21417.

PubMed [citation]

PMID:: 18551513

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV003459823.3

#	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 a region of the LMNA protein in which other variant(s) (p.Lys32del, p.Asn39Ser, p.Glu82Lys) have been determined to be pathogenic (PMID: 17377071, 18551513, 20980393, 21632249). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 200949). This sequence change affects the initiator methionine of the LMNA mRNA. The next in-frame methionine is located at codon 187. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 29211919).

#	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: Feb 20, 2024

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