NM_170707.4(LMNA):c.1381-5G>A AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 18, 2024
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:: RCV000815746.11

Allele description [Variation Report for NM_170707.4(LMNA):c.1381-5G>A]

NM_170707.4(LMNA):c.1381-5G>A

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.1381-5G>A

HGVS:

NC_000001.11:g.156136916G>A
NG_008692.2:g.59344G>A
NM_001257374.3:c.1045-5G>A
NM_001282624.2:c.1138-5G>A
NM_001282625.2:c.1381-5G>A
NM_001282626.2:c.1381-5G>A
NM_005572.4:c.1381-5G>A
NM_170707.4:c.1381-5G>AMANE SELECT
NM_170708.4:c.1381-5G>A
LRG_254t2:c.1381-5G>A
LRG_254:g.59344G>A
NC_000001.10:g.156106707G>A
NM_170707.2:c.1381-5G>A
NM_170707.3:c.1381-5G>A

Links:

dbSNP: rs730880133

NCBI 1000 Genomes Browser:

rs730880133

Molecular consequence:

NM_001257374.3:c.1045-5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001282624.2:c.1138-5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001282625.2:c.1381-5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001282626.2:c.1381-5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_005572.4:c.1381-5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_170707.4:c.1381-5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_170708.4:c.1381-5G>A - intron variant - [Sequence Ontology: SO:0001627]

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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brain-derived neurotrophic factor isoform b precursor [Homo sapiens]
brain-derived neurotrophic factor isoform b precursor [Homo sapiens]
gi|25306235|ref|NP_733927.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000956215	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 18, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 34768595, 28679633, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000956215

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 18, 2024)

germline

clinical testing

PubMed (3)
[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 Features of LMNA-Related Cardiomyopathy in 18 Patients and Characterization of Two Novel Variants.

Ferradini V, Cosma J, Romeo F, De Masi C, Murdocca M, Spitalieri P, Mannucci S, Parlapiano G, Di Lorenzo F, Martino A, Fedele F, Calò L, Novelli G, Sangiuolo F, Mango R.

J Clin Med. 2021 Oct 29;10(21). doi:pii: 5075. 10.3390/jcm10215075.

PubMed [citation]

PMID:: 34768595
PMCID:: PMC8584896

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing.

Ito K, Patel PN, Gorham JM, McDonough B, DePalma SR, Adler EE, Lam L, MacRae CA, Mohiuddin SM, Fatkin D, Seidman CE, Seidman JG.

Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7689-7694. doi: 10.1073/pnas.1707741114. Epub 2017 Jul 5.

PubMed [citation]

PMID:: 28679633
PMCID:: PMC5528995

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000956215.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change falls in intron 7 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs730880133, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 28679633, 34768595). ClinVar contains an entry for this variant (Variation ID: 180405). Studies have shown that this variant results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 28679633). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Jun 23, 2024

ClinVar

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