NM_170707.4(LMNA):c.11C>T (p.Pro4Leu) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 27, 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:: RCV001896572.6

Allele description [Variation Report for NM_170707.4(LMNA):c.11C>T (p.Pro4Leu)]

NM_170707.4(LMNA):c.11C>T (p.Pro4Leu)

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.11C>T (p.Pro4Leu)

HGVS:

NC_000001.11:g.156114929C>T
NG_008692.2:g.37357C>T
NM_001282625.2:c.11C>T
NM_001282626.2:c.11C>T
NM_005572.4:c.11C>T
NM_170707.4:c.11C>TMANE SELECT
NM_170708.4:c.11C>T
NP_001269554.1:p.Pro4Leu
NP_001269555.1:p.Pro4Leu
NP_005563.1:p.Pro4Leu
NP_733821.1:p.Pro4Leu
NP_733822.1:p.Pro4Leu
LRG_254:g.37357C>T
NC_000001.10:g.156084720C>T

Protein change:

P4L

Links:

dbSNP: rs267607620

NCBI 1000 Genomes Browser:

rs267607620

Molecular consequence:

NM_001282625.2:c.11C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.11C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.11C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.11C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.11C>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
SCV002166126	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19875478, 24861648, 31378009, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002166126

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 27, 2023)

germline

clinical testing

PubMed (4)
[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

Atypical progeroid syndrome due to heterozygous missense LMNA mutations.

Garg A, Subramanyam L, Agarwal AK, Simha V, Levine B, D'Apice MR, Novelli G, Crow Y.

J Clin Endocrinol Metab. 2009 Dec;94(12):4971-83. doi: 10.1210/jc.2009-0472. Epub 2009 Oct 29.

PubMed [citation]

PMID:: 19875478
PMCID:: PMC2795646

p.Pro4Arg mutation in LMNA gene: a new atypical progeria phenotype without metabolism abnormalities.

Guo H, Luo N, Hao F, Bai Y.

Gene. 2014 Aug 1;546(1):35-9. doi: 10.1016/j.gene.2014.05.042. Epub 2014 May 23.

PubMed [citation]

PMID:: 24861648

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002166126.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the LMNA protein (p.Pro4Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1393122). 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 with a positive predictive value of 95%. This variant disrupts the p.Pro4 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19875478, 24861648, 31378009). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024

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