NM_001613.4(ACTA2):c.535C>T (p.Arg179Cys) AND Familial aortopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 20, 2018
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:: RCV000780814.4

Allele description [Variation Report for NM_001613.4(ACTA2):c.535C>T (p.Arg179Cys)]

NM_001613.4(ACTA2):c.535C>T (p.Arg179Cys)

Gene:

ACTA2:actin alpha 2, smooth muscle [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_001613.4(ACTA2):c.535C>T (p.Arg179Cys)

HGVS:

NC_000010.11:g.88941310G>A
NG_011541.1:g.55081C>T
NM_001141945.3:c.535C>T
NM_001320855.2:c.535C>T
NM_001406462.1:c.535C>T
NM_001406463.1:c.535C>T
NM_001406464.1:c.535C>T
NM_001406466.1:c.424C>T
NM_001406467.1:c.406C>T
NM_001406468.1:c.406C>T
NM_001406469.1:c.406C>T
NM_001406471.1:c.535C>T
NM_001613.4:c.535C>TMANE SELECT
NP_001135417.1:p.Arg179Cys
NP_001135417.1:p.Arg179Cys
NP_001135417.1:p.Arg179Cys
NP_001307784.1:p.Arg179Cys
NP_001307784.1:p.Arg179Cys
NP_001393391.1:p.Arg179Cys
NP_001393392.1:p.Arg179Cys
NP_001393393.1:p.Arg179Cys
NP_001393395.1:p.Arg142Cys
NP_001393396.1:p.Arg136Cys
NP_001393397.1:p.Arg136Cys
NP_001393398.1:p.Arg136Cys
NP_001393400.1:p.Arg179Cys
NP_001604.1:p.Arg179Cys
NP_001604.1:p.Arg179Cys
LRG_781t1:c.535C>T
LRG_781t2:c.535C>T
LRG_781:g.55081C>T
LRG_781p1:p.Arg179Cys
LRG_781p2:p.Arg179Cys
NC_000010.10:g.90701067G>A
NM_001141945.1:c.535C>T
NM_001141945.2:c.535C>T
NM_001320855.1:c.535C>T
NM_001613.2:c.535C>T

Protein change:

R136C; ARG179CYS

Links:

OMIM: 102620.0008; dbSNP: rs886039303

NCBI 1000 Genomes Browser:

rs886039303

Molecular consequence:

NM_001141945.3:c.535C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320855.2:c.535C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406462.1:c.535C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406463.1:c.535C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406464.1:c.535C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406466.1:c.424C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406467.1:c.406C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406468.1:c.406C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406469.1:c.406C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406471.1:c.535C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001613.4:c.535C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial aortopathy
Identifiers:: MedGen: CN078214

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000918387	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 20, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27481187, 27567161, 23613326 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000918387

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Feb 20, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes.

Moreno CA, Metze K, Lomazi EA, Bertola DR, Barbosa RH, Cosentino V, Sobreira N, Cavalcanti DP.

Am J Med Genet A. 2016 Nov;170(11):2965-2974. doi: 10.1002/ajmg.a.37857. Epub 2016 Aug 2. Review.

PubMed [citation]

PMID:: 27481187
PMCID:: PMC5590821

Cerebral arteriopathy associated with heterozygous Arg179Cys mutation in the ACTA2 gene: Report in 2 newborn siblings.

de Grazia J, Delgado I, Sanchez-Montanez A, Boronat S, Del Campo M, Vazquez E.

Brain Dev. 2017 Jan;39(1):62-66. doi: 10.1016/j.braindev.2016.08.003. Epub 2016 Aug 25.

PubMed [citation]

PMID:: 27567161

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918387.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: ACTA2 c.535C>T (p.Arg179Cys) results in a non-conservative amino acid change in the encoded protein sequence indicated to be located near a key protein-protein interaction site (Moreno_2016). Five of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally asssessed. The variant was absent in 121348 control chromosomes (ExAC). Multiple publications have cited the variant in affected individuals presenting with a multisystemic smooth muscle dysfunction syndrome (MSMDS) and aortic event. Multiple studies indicate the variant was a de novo occurrence (Meuwissen_2012 and Moreno_2016). In addition, other variants affecting the same codon, Arg179His and Arg179Lys, have been reported in affected individuals indicating a potential mutational hot spot. One clinical diagnostic laboratory has submitted a clinical-significance assessments of "likely pathogenic" for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Mar 10, 2024

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