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

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

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:: RCV002399328.3

Allele description

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:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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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

Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy.

Raffaele Di Barletta M, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L, Romorini A, Voit T, Orstavik KH, Merlini L, Trevisan C, Biancalana V, Housmanowa-Petrusewicz I, Bione S, Ricotti R, Schwartz K, Bonne G, Toniolo D.

Am J Hum Genet. 2000 Apr;66(4):1407-12. Epub 2000 Mar 16.

PubMed [citation]

PMID:: 10739764
PMCID:: PMC1288205

Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy.

Brown CA, Lanning RW, McKinney KQ, Salvino AR, Cherniske E, Crowe CA, Darras BT, Gominak S, Greenberg CR, Grosmann C, Heydemann P, Mendell JR, Pober BR, Sasaki T, Shapiro F, Simpson DA, Suchowersky O, Spence JE.

Am J Med Genet. 2001 Sep 1;102(4):359-67.

PubMed [citation]

PMID:: 11503164

See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV002709534.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

The p.R527H variant (also known as c.1580G>A), located in coding exon 9 of the LMNA gene, results from a G to A substitution at nucleotide position 1580. The arginine at codon 527 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in several homozygous individuals with autosomal recessive mandibuloacral dysplasia (MAD) (Shen JJ et al. J. Med. Genet., 2003 Nov;40:854-7; Garavelli L et al. Am. J. Med. Genet. A, 2009 Oct;149A:2258-64; Sakka et al. Eur J Med Genet, 2021 Feb;64:104138; Jéru I et al. Genes (Basel), 2021 Sep;12:[Epub ahead of print]). Compound heterozygosity (p.R527H/p.V440M) has also been reported in an individual with overlapping MAD and laminopathy features that were considered atypical along with a limb-girdle-like myopathy (Lombardi F et al. J. Clin. Endocrinol. Metab., 2007 Nov;92:4467-71). Heterozygous carrier family members and healthy population cohort participants have been reported to be unaffected with MAD or other laminopathy-related phenotypes (Dron JS et al. BMC Med Genomics, 2020 02;13:23; Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51; Sakka et al. Eur J Med Genet, 2021 Feb;64:104138). Functional studies demonstrate that lamin A plays an important role in TGFbeta 2 regulation and that this alteration affects genomic stability and DNA damage response with the accumulation of lamin A precursor protein after X-ray exposure (Novelli G et al. Am. J. Hum. Genet., 2002 Aug;71:426-31; Evangelisti C et al. Oncotarget, 2015 Apr;6:7424-37; di Masi A et al. Cell Cycle, 2008 Jul;7:2030-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of mandibuloacral dysplasia (MAD) when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant laminopathy-related phenotypes is unclear.

#	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
SCV002709534	Ambry Genetics	flagged submission Reason: Unnecessary conflicting claim for distinct condition when other classifications are more relevant Notes: Claim states uncertain significance for laminopathy-related phenotypes, but says that variant is causative for mandibuloacral dysplasia (MAD). https://clinicalgenome.org/site/assets/files/9380/clingen_guidance_for_classifying_variants_in_genes_associated_with_multiple_disorders_v1.pdf (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 28, 2021)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 10739764, 11503164, 12075506, 14627682, 16364671, 17848409, 18604166, 19764019, 25823658, 32041611, 33422685, 33458588, 34135346, 34680903 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002709534

Ambry Genetics

flagged submission

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

Notes: Claim states uncertain significance for laminopathy-related phenotypes, but says that variant is causative for mandibuloacral dysplasia (MAD). https://clinicalgenome.org/site/assets/files/9380/clingen_guidance_for_classifying_variants_in_genes_associated_with_multiple_disorders_v1.pdf

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 28, 2021)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

Citation Link

Last Updated: Dec 22, 2024

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