NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp) AND Emery-Dreifuss muscular dystrophy 2, autosomal dominant

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 2, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000015565.37

Allele description

NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp)

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.1357C>T (p.Arg453Trp)

HGVS:

NC_000001.11:g.156136413C>T
NG_008692.2:g.58841C>T
NM_001257374.3:c.1021C>T
NM_001282624.2:c.1114C>T
NM_001282625.2:c.1357C>T
NM_001282626.2:c.1357C>T
NM_005572.4:c.1357C>T
NM_170707.4:c.1357C>TMANE SELECT
NM_170708.4:c.1357C>T
NP_001244303.1:p.Arg341Trp
NP_001269553.1:p.Arg372Trp
NP_001269554.1:p.Arg453Trp
NP_001269555.1:p.Arg453Trp
NP_005563.1:p.Arg453Trp
NP_733821.1:p.Arg453Trp
NP_733822.1:p.Arg453Trp
LRG_254t2:c.1357C>T
LRG_254:g.58841C>T
NC_000001.10:g.156106204C>T
NM_005572.4:c.1357C>T
NM_170707.2:c.1357C>T
NM_170707.3:c.1357C>T
P02545:p.Arg453Trp

Protein change:

R341W; ARG453TRP

Links:

UniProtKB: P02545#VAR_009988; OMIM: 150330.0002; dbSNP: rs58932704

NCBI 1000 Genomes Browser:

rs58932704

Molecular consequence:

NM_001257374.3:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1114C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functionally_abnormal [Sequence Ontology: SO:0002218]

Observations:

Condition(s)

Name:: Emery-Dreifuss muscular dystrophy 2, autosomal dominant (EDMD2)
Synonyms:: MUSCULAR DYSTROPHY WITH EARLY CONTRACTURES AND CARDIOMYOPATHY, AUTOSOMAL DOMINANT; SCAPULOILIOPERONEAL ATROPHY WITH CARDIOPATHY; Benign scapuloperoneal muscular dystrophy with cardiomyopathy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0021569; MedGen: C0410190; Orphanet: 261; Orphanet: 264; OMIM: 181350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035830	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000265777	Center for Genetic Medicine Research, Children's National Medical Center	criteria provided, single submitter (Punetha et al. (J Neuromuscul Dis. 2016))	Likely pathogenic (Dec 1, 2015)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001251976	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005398764	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10739764, 17377071, 20848652, 32571898, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.

Bonne G, Di Barletta MR, Varnous S, Bécane HM, Hammouda EH, Merlini L, Muntoni F, Greenberg CR, Gary F, Urtizberea JA, Duboc D, Fardeau M, Toniolo D, Schwartz K.

Nat Genet. 1999 Mar;21(3):285-8.

PubMed [citation]

PMID:: 10080180

Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases.

Punetha J, Kesari A, Uapinyoying P, Giri M, Clarke NF, Waddell LB, North KN, Ghaoui R, O'Grady GL, Oates EC, Sandaradura SA, Bönnemann CG, Donkervoort S, Plotz PH, Smith EC, Tesi-Rocha C, Bertorini TE, Tarnopolsky MA, Reitter B, Hausmanowa-Petrusewicz I, Hoffman EP.

J Neuromuscul Dis. 2016 May 27;3(2):209-225.

PubMed [citation]

PMID:: 27854218

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000035830.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a family with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), Bonne et al. (1999) demonstrated a C-to-T transition in exon 7 of the LMNA gene, resulting in an arg453-to-trp (R453W) substitution.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genetic Medicine Research, Children's National Medical Center, SCV000265777.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, SCV001251976.1

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

Description

The presence of a disease-causing variant was detected in exon 7 of the LMNA gene. The name of the variant is: NM_170707:c.1357C> T;p.Arg453Trp. In the parents, this variant could not be detected in 21 reads each, which is why it is very likely that the patient developed it anew (de novo). This variant is not listed in population-based databases (gnomAD, ExAC, EVS and 1000Genomes). In dbSNP it is listed under the rs number rs58932704 . In the phanotype-related databases LOVD, HGMD and ClinVar the variant is already listed several times and is generally considered to be mainly pathogenic, but also probably pathogenic. The mutation prediction programs MutationTaster, SIFT, PROVEAN and PolyPhen-2 assess the variant as pathogenic, the CADD score is 34. In order to assess the possible disturbance of splice behavior by the above-mentioned variant, we have used various programs for the prediction of splice sites and splice enhancers with the aid of the Alamut software. The in-silica analysis does not provide any significant indication of a change in splice1 behavior. Functional studies have shown significant effects of this variant on protein function (e.g. PMID 21173262, 14749366, 20980393, 25948554). The ACMG classification for this variant is: pathogenic (class 5; PS2 PS3 PM2 PP3 PP5).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005398764.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Some missense variants have been reported to result in a toxic gain of function or dominant negative and are associated with childhood-onset disease or skeletal muscle involvement, while other variants have been reported to result in a loss of function and haploinsufficiency, and are associated with adult-onset disease, cardiac disorders or myopathy (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease. However, a clear genotype-phenotpe correlation is yet to be established. (I) 0112 - The condition associated with this gene has incomplete penetrance. Emery-Dreifuss muscular dystrophy has been reported to have reduced penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated lamin tail domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is frequently reported in individuals with autosomal dominant Emery-Dreifuss muscular dystrophy 2 (MIM#181350), including de novo events (PMID: 10739764, 20848652, 32571898; ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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