NM_170707.4(LMNA):c.1772G>T (p.Cys591Phe) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 3, 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:: RCV003581576.2

Allele description [Variation Report for NM_170707.4(LMNA):c.1772G>T (p.Cys591Phe)]

NM_170707.4(LMNA):c.1772G>T (p.Cys591Phe)

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.1772G>T (p.Cys591Phe)

HGVS:

NC_000001.11:g.156138561G>T
NG_008692.2:g.60989G>T
NM_001257374.3:c.1436G>T
NM_001282626.2:c.1772G>T
NM_170707.4:c.1772G>TMANE SELECT
NM_170708.4:c.1682G>T
NP_001244303.1:p.Cys479Phe
NP_001269555.1:p.Cys591Phe
NP_733821.1:p.Cys591Phe
NP_733822.1:p.Cys561Phe
LRG_254t2:c.1772G>T
LRG_254:g.60989G>T
NC_000001.10:g.156108352G>T
NM_170707.2:c.1772G>T

Protein change:

C479F

Links:

dbSNP: rs267607556

NCBI 1000 Genomes Browser:

rs267607556

Molecular consequence:

NM_001257374.3:c.1436G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1772G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1772G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1682G>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
SCV004292927	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18031308, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004292927

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 3, 2023)

germline

clinical testing

PubMed (2)
[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

A novel phenotypic expression associated with a new mutation in LMNA gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy.

Araújo-Vilar D, Lado-Abeal J, Palos-Paz F, Lattanzi G, Bandín MA, Bellido D, Domínguez-Gerpe L, Calvo C, Pérez O, Ramazanova A, Martínez-Sánchez N, Victoria B, Costa-Freitas AT.

Clin Endocrinol (Oxf). 2008 Jul;69(1):61-8. Epub 2008 Jul 1.

PubMed [citation]

PMID:: 18031308

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, SCV004292927.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Experimental studies have shown that this missense change affects LMNA function (PMID: 18031308). 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. 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: 66866). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 18031308). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 591 of the LMNA protein (p.Cys591Phe).

#	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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