NM_001613.4(ACTA2):c.146T>C (p.Met49Thr) AND Aortic aneurysm, familial thoracic 6

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 29, 2023
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:: RCV002531810.9

Allele description [Variation Report for NM_001613.4(ACTA2):c.146T>C (p.Met49Thr)]

NM_001613.4(ACTA2):c.146T>C (p.Met49Thr)

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.146T>C (p.Met49Thr)

HGVS:

NC_000010.11:g.88947370A>G
NG_011541.1:g.49021T>C
NM_001141945.3:c.146T>C
NM_001320855.2:c.146T>C
NM_001406462.1:c.146T>C
NM_001406463.1:c.146T>C
NM_001406464.1:c.146T>C
NM_001406466.1:c.146T>C
NM_001406471.1:c.146T>C
NM_001613.4:c.146T>CMANE SELECT
NP_001135417.1:p.Met49Thr
NP_001135417.1:p.Met49Thr
NP_001135417.1:p.Met49Thr
NP_001307784.1:p.Met49Thr
NP_001307784.1:p.Met49Thr
NP_001393391.1:p.Met49Thr
NP_001393392.1:p.Met49Thr
NP_001393393.1:p.Met49Thr
NP_001393395.1:p.Met49Thr
NP_001393400.1:p.Met49Thr
NP_001604.1:p.Met49Thr
NP_001604.1:p.Met49Thr
LRG_781t1:c.146T>C
LRG_781t2:c.146T>C
LRG_781:g.49021T>C
LRG_781p1:p.Met49Thr
LRG_781p2:p.Met49Thr
NC_000010.10:g.90707127A>G
NM_001141945.1:c.146T>C
NM_001141945.2:c.146T>C
NM_001320855.1:c.146T>C
NM_001613.2:c.146T>C

Protein change:

M49T

Links:

dbSNP: rs869025352

NCBI 1000 Genomes Browser:

rs869025352

Molecular consequence:

NM_001141945.3:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001320855.2:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406462.1:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406463.1:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406464.1:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406466.1:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406471.1:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001613.4:c.146T>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003309767	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 29, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21248741, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003309767

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 29, 2023)

germline

clinical testing

PubMed (2)
[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

Citations

PubMed

Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections.

Hoffjan S, Waldmüller S, Blankenfeldt W, Kötting J, Gehle P, Binner P, Epplen JT, Scheffold T.

Eur J Hum Genet. 2011 May;19(5):520-4. doi: 10.1038/ejhg.2010.239. Epub 2011 Jan 19.

PubMed [citation]

PMID:: 21248741
PMCID:: PMC3083620

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003309767.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

ClinVar contains an entry for this variant (Variation ID: 519576). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 49 of the ACTA2 protein (p.Met49Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ACTA2-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. 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 not expected to disrupt ACTA2 protein function. This variant disrupts the p.Met49 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been observed in individuals with ACTA2-related conditions (PMID: 21248741), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: May 1, 2024

ClinVar

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