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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 8, 2019
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:: RCV000148607.5

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:: Mandibuloacral dysplasia (MADA)
Synonyms:: Mandibuloacral dysostosis
Identifiers:: MONDO: MONDO:0016584; MedGen: C0432291; OMIM: PS248370

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190322	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV004848697	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 8, 2019)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 12075506, 14627682, 12788894, 17848409, 16046620, 28349240, 24375749, 15473259, 18604166, 25823658, 16809772, 19764019, 25324471, 28663758, 17274801, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190322

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV004848697

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 8, 2019)

germline

clinical testing

PubMed (16)
[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, research

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 (16)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190322.1

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

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848697.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

The p.Arg527His variant in LMNA has been reported in the homozygous or compound heterozygous state in 10 individuals with mandiculoacral dysplasia (MAD) and segregated with disease in 5 affected individuals from 4 families (Novelli 2002, Shen 2003, Simha 2003, Garavelli 2009). It has also been identified in 6/31826 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 14499). In vitro functional studies support an impact on protein function (Novelli 2002, Amati 2004, Filesi 2005, Nitta 2006, Lombardi 2007, Meaburn 2007, di Masi 2008, Evangelisti 2015). Three additional variants involving this codon (p.Arg527) have been identified in individuals with MAD (Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MAD. ACMG/AMP Criteria applied: PM3_VeryStrong, PS4, PM5_Strong, PP1_Strong, PS3_Moderate, BP4.

#	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: Dec 22, 2024

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