NM_170707.4(LMNA):c.1580G>A (p.Arg527His) AND Cardiomyopathy

Germline classification:: no classifications from unflagged records (1 submission)
Last evaluated:: Jun 14, 2024
Review status:: no classifications from unflagged records

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:: RCV001178367.5

Allele description [Variation Report for NM_170707.4(LMNA):c.1580G>A (p.Arg527His)]

NM_170707.4(LMNA):c.1580G>A (p.Arg527His)

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.1580G>A (p.Arg527His)

Other names:

p.R527H:CGT>CAT

HGVS:

NC_000001.11:g.156137204G>A
NG_008692.2:g.59632G>A
NM_001257374.3:c.1244G>A
NM_001282624.2:c.1337G>A
NM_001282625.2:c.1580G>A
NM_001282626.2:c.1580G>A
NM_005572.4:c.1580G>A
NM_170707.4:c.1580G>AMANE SELECT
NM_170708.4:c.1580G>A
NP_001244303.1:p.Arg415His
NP_001269553.1:p.Arg446His
NP_001269554.1:p.Arg527His
NP_001269555.1:p.Arg527His
NP_005563.1:p.Arg527His
NP_005563.1:p.Arg527His
NP_733821.1:p.Arg527His
NP_733822.1:p.Arg527His
LRG_254t1:c.1580G>A
LRG_254t2:c.1580G>A
LRG_254:g.59632G>A
LRG_254p1:p.Arg527His
NC_000001.10:g.156106995G>A
NM_001257374.1:c.1244G>A
NM_005572.3:c.1580G>A
NM_170707.2:c.1580G>A
NM_170707.3:c.1580G>A
P02545:p.Arg527His

Protein change:

R415H; ARG527HIS

Links:

UniProtKB: P02545#VAR_018727; OMIM: 150330.0021; dbSNP: rs57520892

NCBI 1000 Genomes Browser:

rs57520892

Molecular consequence:

NM_001257374.3:c.1244G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1580G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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No clinical assertions found. See "Flagged submissions" below.

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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

Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C.

Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D'Apice MR, Massart C, Capon F, Sbraccia P, Federici M, Lauro R, Tudisco C, Pallotta R, Scarano G, Dallapiccola B, Merlini L, Bonne G.

Am J Hum Genet. 2002 Aug;71(2):426-31. Epub 2002 Jun 19.

PubMed [citation]

PMID:: 12075506
PMCID:: PMC379176

Mandibuloacral dysplasia caused by homozygosity for the R527H mutation in lamin A/C.

Shen JJ, Brown CA, Lupski JR, Potocki L.

J Med Genet. 2003 Nov;40(11):854-7. No abstract available.

PubMed [citation]

PMID:: 14627682
PMCID:: PMC1735303

See all PubMed Citations (12)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001342797.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This missense variant replaces arginine with histidine at codon 527 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In a transgenic mouse model, this variant has been associated with phenotypes relevant for mandibuloacral dysplasia type A syndrome while muscle phenotypes are normal (PMID: 33458588). Fibroblast cell cultures from the transgenic mice displayed nuclear envelope aberrations, accumulation of the lamin A precursor protein, proliferation, and senescence rate defects (PMID: 33458588). Another functional study has shown that cells from a homozygous carrier show abnormal nuclear morphology, while cells from a heterozygous carrier show normal nuclear morphology (PMID: 12075506). Other functional studies have suggested that this variant may increase sensitivity to ionizing radiation (PMID:18604166), affect DNA synthesis (PMID 25324471) and fail to downregulate TGFbeta-2 secretion (PMID: 25823658). This variant has been associated with autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease in several families and has been reported in the homozygous or compound heterozygous states in multiple affected individuals (PMID: 12075506, 14627682, 25286833, 32376792, 33038109, 33422685, 34680903, Xu et al. 2019 doi: 10.3969/j.issn.1000-3606.2019.09.010). Most affected carriers showed no signs of cardiac involvement except for one individual who was also affected with dilated cardiomyopathy (PMID: 33422685). Heterozygous parents were reported to be healthy. This variant has also been identified in 10/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease (ClinVar variation ID: 14499).

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001342797	Color Diagnostics, LLC DBA Color Health	flagged submission Reason: Unnecessary conflicting claim for distinct condition when other classifications are more relevant Notes: Claim states uncertain significance for cardiomyopathy, but says that variant is causative for mandibuloacral dysplasia and Charcot-Marie-Tooth disease. https://clinicalgenome.org/site/assets/files/9380/clingen_guidance_for_classifying_variants_in_genes_associated_with_multiple_disorders_v1.pdf (ACMG Guidelines, 2015)	Uncertain significance (May 16, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 12075506, 14627682, 18604166, 25286833, 25324471, 25823658, 32376792, 33038109, 33422685, 33458588, 34680903, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001342797

Color Diagnostics, LLC DBA Color Health

flagged submission

Reason: Unnecessary conflicting claim for distinct condition when other classifications are more relevant

Notes: Claim states uncertain significance for cardiomyopathy, but says that variant is causative for mandibuloacral dysplasia and Charcot-Marie-Tooth disease. https://clinicalgenome.org/site/assets/files/9380/clingen_guidance_for_classifying_variants_in_genes_associated_with_multiple_disorders_v1.pdf

(ACMG Guidelines, 2015)

Uncertain significance
(May 16, 2023)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

Last Updated: Jan 13, 2025

ClinVar

Relating variation to medicine