NM_170707.4(LMNA):c.1262T>C (p.Leu421Pro) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 9, 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:: RCV000694118.6

Allele description [Variation Report for NM_170707.4(LMNA):c.1262T>C (p.Leu421Pro)]

NM_170707.4(LMNA):c.1262T>C (p.Leu421Pro)

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.1262T>C (p.Leu421Pro)

HGVS:

NC_000001.11:g.156136318T>C
NG_008692.2:g.58746T>C
NM_001257374.3:c.926T>C
NM_001282624.2:c.1019T>C
NM_001282625.2:c.1262T>C
NM_001282626.2:c.1262T>C
NM_005572.4:c.1262T>C
NM_170707.4:c.1262T>CMANE SELECT
NM_170708.4:c.1262T>C
NP_001244303.1:p.Leu309Pro
NP_001269553.1:p.Leu340Pro
NP_001269554.1:p.Leu421Pro
NP_001269555.1:p.Leu421Pro
NP_005563.1:p.Leu421Pro
NP_733821.1:p.Leu421Pro
NP_733822.1:p.Leu421Pro
LRG_254t2:c.1262T>C
LRG_254:g.58746T>C
NC_000001.10:g.156106109T>C
NM_170707.2:c.1262T>C
NM_170707.3:c.1262T>C
P02545:p.Leu421Pro

Protein change:

L309P

Links:

UniProtKB: P02545#VAR_072823; dbSNP: rs267607564

NCBI 1000 Genomes Browser:

rs267607564

Molecular consequence:

NM_001257374.3:c.926T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1019T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1262T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1262T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1262T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1262T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1262T>C - 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
SCV000822547	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 9, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17612587, 23977161, 24943589, 17711925, 32376792, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000822547

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 9, 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

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence.

Caron M, Auclair M, Donadille B, Béréziat V, Guerci B, Laville M, Narbonne H, Bodemer C, Lascols O, Capeau J, Vigouroux C.

Cell Death Differ. 2007 Oct;14(10):1759-67. Epub 2007 Jul 6.

PubMed [citation]

PMID:: 17612587

Mutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations.

Yang L, Munck M, Swaminathan K, Kapinos LE, Noegel AA, Neumann S.

PLoS One. 2013;8(8):e71850. doi: 10.1371/journal.pone.0071850.

PubMed [citation]

PMID:: 23977161
PMCID:: PMC3748058

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000822547.6

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

Description

Experimental studies have shown that this missense change affects LMNA function (PMID: 17612587, 23977161, 24943589). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 66798). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 17711925, 32376792). This variant is present in population databases (rs267607564, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 421 of the LMNA protein (p.Leu421Pro). 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: Apr 20, 2024

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