NM_170707.4(LMNA):c.1412G>A (p.Arg471His) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 6, 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:: RCV000653872.10

Allele description [Variation Report for NM_170707.4(LMNA):c.1412G>A (p.Arg471His)]

NM_170707.4(LMNA):c.1412G>A (p.Arg471His)

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.1412G>A (p.Arg471His)

Other names:

p.R471H:CGC>CAC

HGVS:

NC_000001.11:g.156136952G>A
NG_008692.2:g.59380G>A
NM_001257374.3:c.1076G>A
NM_001282624.2:c.1169G>A
NM_001282625.2:c.1412G>A
NM_001282626.2:c.1412G>A
NM_005572.4:c.1412G>A
NM_170707.4:c.1412G>AMANE SELECT
NM_170708.4:c.1412G>A
NP_001244303.1:p.Arg359His
NP_001269553.1:p.Arg390His
NP_001269554.1:p.Arg471His
NP_001269555.1:p.Arg471His
NP_005563.1:p.Arg471His
NP_005563.1:p.Arg471His
NP_733821.1:p.Arg471His
NP_733822.1:p.Arg471His
LRG_254t1:c.1412G>A
LRG_254t2:c.1412G>A
LRG_254t3:c.1412G>A
LRG_254:g.59380G>A
LRG_254p1:p.Arg471His
NC_000001.10:g.156106743G>A
NM_005572.3:c.1412G>A
NM_170707.2:c.1412G>A
NM_170707.3:c.1412G>A
NM_170708.2:c.1412G>A
P02545:p.Arg471His
c.1412G>A

Protein change:

R359H

Links:

UniProtKB: P02545#VAR_070182; dbSNP: rs267607578

NCBI 1000 Genomes Browser:

rs267607578

Molecular consequence:

NM_001257374.3:c.1076G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1412G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1412G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1412G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1412G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1412G>A - 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
SCV000775762	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 6, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18646565, 22177269, 23582089, 27532257, 29943882, 20160190, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000775762

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 6, 2024)

germline

clinical testing

PubMed (7)
[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

Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan.

Astejada MN, Goto K, Nagano A, Ura S, Noguchi S, Nonaka I, Nishino I, Hayashi YK.

Acta Myol. 2007 Dec;26(3):159-64. Review.

PubMed [citation]

PMID:: 18646565
PMCID:: PMC2949309

Molecular autopsy in young sudden cardiac death victims with suspected cardiomyopathy.

Larsen MK, Nissen PH, Berge KE, Leren TP, Kristensen IB, Jensen HK, Banner J.

Forensic Sci Int. 2012 Jun 10;219(1-3):33-8. doi: 10.1016/j.forsciint.2011.11.020. Epub 2011 Dec 15.

PubMed [citation]

PMID:: 22177269

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000775762.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 471 of the LMNA protein (p.Arg471His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant dilated cardiomyopathy and limb-girdle muscular dystrophy (PMID: 18646565, 22177269, 23582089, 27532257, 29943882). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36476). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 20160190). For these reasons, this variant has been classified as Pathogenic.

#	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: May 1, 2024

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