NM_170707.4(LMNA):c.1115A>T (p.Glu372Val) 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:: RCV001366528.7

Allele description [Variation Report for NM_170707.4(LMNA):c.1115A>T (p.Glu372Val)]

NM_170707.4(LMNA):c.1115A>T (p.Glu372Val)

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.1115A>T (p.Glu372Val)

HGVS:

NC_000001.11:g.156136079A>T
NG_008692.2:g.58507A>T
NM_001257374.3:c.779A>T
NM_001282624.2:c.872A>T
NM_001282625.2:c.1115A>T
NM_001282626.2:c.1115A>T
NM_005572.4:c.1115A>T
NM_170707.4:c.1115A>TMANE SELECT
NM_170708.4:c.1115A>T
NP_001244303.1:p.Glu260Val
NP_001269553.1:p.Glu291Val
NP_001269554.1:p.Glu372Val
NP_001269555.1:p.Glu372Val
NP_005563.1:p.Glu372Val
NP_733821.1:p.Glu372Val
NP_733822.1:p.Glu372Val
LRG_254t2:c.1115A>T
LRG_254:g.58507A>T
NC_000001.10:g.156105870A>T
NM_170707.2:c.1115A>T

Protein change:

E260V

Links:

dbSNP: rs2102888292

NCBI 1000 Genomes Browser:

rs2102888292

Molecular consequence:

NM_001257374.3:c.779A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1115A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1115A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1115A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1115A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1115A>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
SCV001562833	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001562833

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001562833.4

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

Description

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. This variant disrupts the p.Glu372 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 1057529). 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 glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 372 of the LMNA protein (p.Glu372Val).

#	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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