NM_170707.4(LMNA):c.116A>T (p.Asn39Ile) 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:: RCV000804081.6

Allele description [Variation Report for NM_170707.4(LMNA):c.116A>T (p.Asn39Ile)]

NM_170707.4(LMNA):c.116A>T (p.Asn39Ile)

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.116A>T (p.Asn39Ile)

HGVS:

NC_000001.11:g.156115034A>T
NG_008692.2:g.37462A>T
NM_001282625.2:c.116A>T
NM_001282626.2:c.116A>T
NM_005572.4:c.116A>T
NM_170707.4:c.116A>TMANE SELECT
NM_170708.4:c.116A>T
NP_001269554.1:p.Asn39Ile
NP_001269555.1:p.Asn39Ile
NP_005563.1:p.Asn39Ile
NP_733821.1:p.Asn39Ile
NP_733822.1:p.Asn39Ile
LRG_254:g.37462A>T
NC_000001.10:g.156084825A>T
NM_170707.3:c.116A>T

Protein change:

N39I

Links:

dbSNP: rs57983345

NCBI 1000 Genomes Browser:

rs57983345

Molecular consequence:

NM_001282625.2:c.116A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.116A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.116A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.116A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.116A>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
SCV000943975	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17377071, 18551513, 20837309, 21632249, 24508248, 26098624, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000943975

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (7)
[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 (7)

Details of each submission

From Invitae, SCV000943975.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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: 649203). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 39 of the LMNA protein (p.Asn39Ile). This variant disrupts the p.Asn39 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17377071, 18551513, 20837309, 21632249, 24508248, 26098624). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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 28, 2024

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