NM_001613.4(ACTA2):c.166G>A (p.Val56Met) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 22, 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:: RCV003528720.2

Allele description [Variation Report for NM_001613.4(ACTA2):c.166G>A (p.Val56Met)]

NM_001613.4(ACTA2):c.166G>A (p.Val56Met)

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.166G>A (p.Val56Met)

HGVS:

NC_000010.11:g.88947350C>T
NG_011541.1:g.49041G>A
NM_001141945.3:c.166G>A
NM_001320855.2:c.166G>A
NM_001406462.1:c.166G>A
NM_001406463.1:c.166G>A
NM_001406464.1:c.166G>A
NM_001406466.1:c.166G>A
NM_001406467.1:c.129+1452G>A
NM_001406468.1:c.129+1452G>A
NM_001406469.1:c.129+1452G>A
NM_001406471.1:c.166G>A
NM_001613.4:c.166G>AMANE SELECT
NP_001135417.1:p.Val56Met
NP_001135417.1:p.Val56Met
NP_001307784.1:p.Val56Met
NP_001393391.1:p.Val56Met
NP_001393392.1:p.Val56Met
NP_001393393.1:p.Val56Met
NP_001393395.1:p.Val56Met
NP_001393400.1:p.Val56Met
NP_001604.1:p.Val56Met
NP_001604.1:p.Val56Met
LRG_781t1:c.166G>A
LRG_781t2:c.166G>A
LRG_781:g.49041G>A
LRG_781p1:p.Val56Met
LRG_781p2:p.Val56Met
NC_000010.10:g.90707107C>T
NM_001141945.1:c.166G>A
NM_001613.2:c.166G>A
NM_001613.2:c.166G>A

Protein change:

V56M

Molecular consequence:

NM_001406467.1:c.129+1452G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001406468.1:c.129+1452G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001406469.1:c.129+1452G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001141945.3:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320855.2:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406462.1:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406463.1:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406464.1:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406466.1:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406471.1:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001613.4:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

Recent activity

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pumilio homolog 1 isoform X33 [Mus musculus]
pumilio homolog 1 isoform X33 [Mus musculus]
gi|1907157902|ref|XP_036020463.1|

Protein
Homo sapiens keratin associated protein 11-1 (KRTAP11-1), mRNA
Homo sapiens keratin associated protein 11-1 (KRTAP11-1), mRNA
gi|1653961102|ref|NM_175858.3|

Nucleotide
LOC4333000 [Oryza sativa Japonica Group]
LOC4333000 [Oryza sativa Japonica Group]
Gene ID:4333000

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004362675	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005017904	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 22, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004362675

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 14, 2022)

germline

clinical testing

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

SCV005017904

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 22, 2023)

germline

clinical testing

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV004362675.1

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

Description

This missense variant replaces valine with methionine at codon 56 of the ACTA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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 Ambry Genetics, SCV005017904.1

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

Description

The p.V56M variant (also known as c.166G>A), located in coding exon 2 of the ACTA2 gene, results from a G to A substitution at nucleotide position 166. The valine at codon 56 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains 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

Last Updated: May 7, 2024

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