NM_170707.4(LMNA):c.1567G>A (p.Gly523Arg) AND Cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 10, 2023
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:: RCV001181346.5

Allele description [Variation Report for NM_170707.4(LMNA):c.1567G>A (p.Gly523Arg)]

NM_170707.4(LMNA):c.1567G>A (p.Gly523Arg)

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.1567G>A (p.Gly523Arg)

HGVS:

NC_000001.11:g.156137191G>A
NG_008692.2:g.59619G>A
NM_001257374.3:c.1231G>A
NM_001282624.2:c.1324G>A
NM_001282625.2:c.1567G>A
NM_001282626.2:c.1567G>A
NM_005572.4:c.1567G>A
NM_170707.4:c.1567G>AMANE SELECT
NM_170708.4:c.1567G>A
NP_001244303.1:p.Gly411Arg
NP_001269553.1:p.Gly442Arg
NP_001269554.1:p.Gly523Arg
NP_001269555.1:p.Gly523Arg
NP_005563.1:p.Gly523Arg
NP_733821.1:p.Gly523Arg
NP_733822.1:p.Gly523Arg
LRG_254t2:c.1567G>A
LRG_254:g.59619G>A
NC_000001.10:g.156106982G>A
NM_170707.2:c.1567G>A
NM_170707.3:c.1567G>A
P02545:p.Gly523Arg
c.1567G>A

Protein change:

G411R

Links:

UniProtKB: P02545#VAR_067258; dbSNP: rs201583907

NCBI 1000 Genomes Browser:

rs201583907

Molecular consequence:

NM_001257374.3:c.1231G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1324G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1567G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1567G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1567G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1567G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1567G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001346472	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 10, 2023)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 19318026, 21846512, 24503780, 24623722, 26404900, 28663758, 29961767, 30919684, 31383942, 31744510, 32193531, 32826072, 34720847, 35026164, 25741868
SCV004240717	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 8, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001346472

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 10, 2023)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV004240717

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 8, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Validation of high-resolution DNA melting analysis for mutation scanning of the LMNA gene.

Millat G, Chanavat V, Julia S, Crehalet H, Bouvagnet P, Rousson R.

Clin Biochem. 2009 Jun;42(9):892-8. doi: 10.1016/j.clinbiochem.2009.01.016. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318026

Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy.

Millat G, Bouvagnet P, Chevalier P, Sebbag L, Dulac A, Dauphin C, Jouk PS, Delrue MA, Thambo JB, Le Metayer P, Seronde MF, Faivre L, Eicher JC, Rousson R.

Eur J Med Genet. 2011 Nov-Dec;54(6):e570-5. doi: 10.1016/j.ejmg.2011.07.005. Epub 2011 Aug 4.

PubMed [citation]

PMID:: 21846512

See all PubMed Citations (15)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001346472.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

This missense variant replaces glycine with arginine at codon 523 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study using a yeast two hybrid system has shown that this variant may lead to ~5% lost protein interactions (PMID: 24623722), but functional and clinical significance of this observation is not known. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19318026, 21846512, 24503780, 29961767, 30919684, 31383942), in an individual affected with hypertrophic cardiomyopathy (PMID: 35026164), and in individuals affected with limb girdle muscular dystrophy (PMID: 26404900, 34720847). This variant has been reported in four members of one family (PMID: 30919684); one carrier was affected with subtle right ventricular abnormalities, and the carrier's parent was affected with dilated cardiomyopathy and conduction disease. This variant has also been reported in individuals affected with laminopathy (PMID: 28663758, 31744510, 32193531, 32826072), in individuals affected with chronic kidney disease (PMID: 31383942), and in multiple apparently healthy individuals in a large biobank (PMID: 31383942). This variant has been identified in 22/264998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV004240717.1

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

#	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 7, 2024

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