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NM_001613.4(ACTA2):c.136A>G (p.Met46Val) AND Aortic aneurysm, familial thoracic 6

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Oct 14, 2021
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:
RCV001923663.5

Allele description [Variation Report for NM_001613.4(ACTA2):c.136A>G (p.Met46Val)]

NM_001613.4(ACTA2):c.136A>G (p.Met46Val)

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.136A>G (p.Met46Val)
HGVS:
  • NC_000010.11:g.88947380T>C
  • NG_011541.1:g.49011A>G
  • NM_001141945.3:c.136A>G
  • NM_001320855.2:c.136A>G
  • NM_001406462.1:c.136A>G
  • NM_001406463.1:c.136A>G
  • NM_001406464.1:c.136A>G
  • NM_001406466.1:c.136A>G
  • NM_001406471.1:c.136A>G
  • NM_001613.4:c.136A>GMANE SELECT
  • NP_001135417.1:p.Met46Val
  • NP_001135417.1:p.Met46Val
  • NP_001135417.1:p.Met46Val
  • NP_001307784.1:p.Met46Val
  • NP_001307784.1:p.Met46Val
  • NP_001393391.1:p.Met46Val
  • NP_001393392.1:p.Met46Val
  • NP_001393393.1:p.Met46Val
  • NP_001393395.1:p.Met46Val
  • NP_001393400.1:p.Met46Val
  • NP_001604.1:p.Met46Val
  • NP_001604.1:p.Met46Val
  • LRG_781t1:c.136A>G
  • LRG_781t2:c.136A>G
  • LRG_781:g.49011A>G
  • LRG_781p1:p.Met46Val
  • LRG_781p2:p.Met46Val
  • NC_000010.10:g.90707137T>C
  • NM_001141945.1:c.136A>G
  • NM_001141945.2:c.136A>G
  • NM_001320855.1:c.136A>G
  • NM_001613.2:c.136A>G
Protein change:
M46V
Links:
dbSNP: rs2133270221
NCBI 1000 Genomes Browser:
rs2133270221
Molecular consequence:
  • NM_001141945.3:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320855.2:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406462.1:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406463.1:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406464.1:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406466.1:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406471.1:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001613.4:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Aortic aneurysm, familial thoracic 6 (AAT6)
Synonyms:
FAMILIAL THORACIC AORTIC ANEURYSM WITH LIVEDO RETICULARIS AND IRIS FLOCCULI
Identifiers:
MONDO: MONDO:0012730; MedGen: C2673186; OMIM: 611788

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002194933Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Oct 14, 2021) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Characteristic Cerebrovascular Findings Associated with ACTA2 Gene Mutations.

Zhang A, Jo A, Grajewski K, Kim J.

Can J Neurol Sci. 2019 May;46(3):342-343. doi: 10.1017/cjn.2019.20. Epub 2019 Apr 12.

PubMed [citation]
PMID:
30975232

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002194933.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Met46 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been observed in individuals with ACTA2-related conditions (PMID: 30975232), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACTA2 protein function. This missense change has been observed in individual(s) with clinical features of ACTA2-related conditions (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 46 of the ACTA2 protein (p.Met46Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024