10-88943813-C-T

Position:

chr10-88943813-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001613.4(ACTA2):c.353G>A(p.Arg118Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACTA2
NM_001613.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

ACTA2 (HGNC:130): (actin alpha 2, smooth muscle) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]

ACTA2 links:

STAMBPL1 (HGNC:24105): (STAM binding protein like 1) Predicted to enable Lys63-specific deubiquitinase activity and thiol-dependent deubiquitinase. Predicted to be involved in protein K63-linked deubiquitination. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

STAMBPL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTA2. . Trascript score misZ 4.6117 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome, Moyamoya disease 5.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 10-88943813-C-T is Pathogenic according to our data. Variant chr10-88943813-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA2	NM_001613.4 linkuse as main transcript	c.353G>A	p.Arg118Gln	missense_variant	4/9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10 linkuse as main transcript	c.353G>A	p.Arg118Gln	missense_variant	4/9	1	NM_001613.4	ENSP00000224784	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251034

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135650

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 09, 2017	The p.R118Q pathogenic mutation (also known as c.353G>A), located in coding exon 3 of the ACTA2 gene, results from a G to A substitution at nucleotide position 353. The arginine at codon 118 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported to segregate with thoracic aortic aneurysm and dissection in multiple families (Guo DC et al. Nat. Genet., 2007 Dec;39:1488-93; Guo DC et al. Am. J. Hum. Genet., 2009 May;84:617-27; Bee KJ et al. Circ Cardiovasc Genet, 2012 Dec;5:621-9). Moreover, in vitro studies have suggested that this alteration would affect actin assembly (Guo DC et al. Nat. Genet., 2007 Dec;39:1488-93; Bergeron SE et al. J. Biol. Chem., 2011 Apr;286:11356-69). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 23, 2020	This missense variant replaces arginine with glutamine at codon 118 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). Functional studies in yeast and cultured smooth muscle cells have shown that this variant affects actin assembly or stability (PMID: 17994018, 21288906). It has been shown that this variant segregates with thoracic aortic aneurysm and aortic dissection (TAAD) in three families (PMID: 17994018, 19409525, 23099432). This variant has also been reported in 9 related individuals affected with TAAD and/or coronary artery disease (PMID: 32093627). This variant has been identified in 1/251034 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2024	Variant summary: ACTA2 c.353G>A (p.Arg118Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251034 control chromosomes. c.353G>A has been reported in the literature in the heterozygous state segregating with disease in multiple individuals affected with Thoracic Aortic Aneurysms And Dissections and Early-Onset Coronary Heart Disease (example, Guo_2009, Bee_2012), with at least 1 publication suggesting incomplete penetrance. Experimental evidence in a yeast background suggests that this variant has significant impacts on actin polymerization and function (example, Bergeron_2011). The following publications have been ascertained in the context of this evaluation (PMID: 23099432, 21288906, 19409525). ClinVar contains an entry for this variant (Variation ID: 199670). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 22, 2016	The p.Arg118Gln variant in ACTA2 has been reported in 3 individuals with thoraci c aortic aneurysms and dissections (TAAD) and segregated with disease in 6 affec ted relatives from 3 families (Guo 2007, Gou 2009, Bee 2012). Furthermore, 2 add itional relatives with premature coronary artery disease also carried the varian t (Gou 2009). This variant has also been identified in 1/111342 European chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs112602953). Studies on cultured smooth muscle cells (SMCs) derived fr om a heterozygous carrier of this variant suggest that this variant perturbs ACT A2 filament assembly or stability (Guo 2007). In summary, this variant meets cri teria to be classified as pathogenic for familial TAAD in an autosomal dominant manner based upon segregation studies, low frequency in controls and functional evidence. ACMG/AMP criteria applied: PP1_Strong, PM2, PS3_Moderate, PP4, PS4_Sup porting. -

Aortic aneurysm, familial thoracic 6

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with familial thoracic aortic aneurysm 6 (MIM#611788), Moyamoya disease 5 (MIM#614042) and multisystemic smooth muscle dysfunction syndrome (MIM#613834) (PMID: 27551047, 28652363). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated actin domain (NCBI). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change to a tryptophan has been reported once as a VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with familial thoracic aortic aneurysm (ClinVar, PMID: 17994018, 25759435). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional study using smooth muscle cells suggested that variant perturbs ACTA2 filament assembly or stability (PMID: 17994018). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 118 of the ACTA2 protein (p.Arg118Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with increased risk of coronary artery disease and/or thoracic aortic dissections (PMID: 17994018, 19409525, 21248741, 25759435). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199670). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACTA2 protein function. Experimental studies have shown that this missense change affects ACTA2 function (PMID: 21288906). For these reasons, this variant has been classified as Pathogenic. -

Aortic aneurysm, familial thoracic 6;C3151201:Multisystemic smooth muscle dysfunction syndrome;C3279690:Moyamoya disease 5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 23, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 03, 2021

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic by several other clinical laboratories (ClinVar Variant ID# 199670; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 17994018, 21288906, 23099432, 28848449, 29727688, 20734336, 20689142, 21248741, 22946110, 25759435, 19409525, 31447099, 34244757) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Pathogenic

0.94

Sift4G

Uncertain

0.0070

D;.;.

Polyphen

0.94

P;.;.

Vest4

0.93

MutPred

0.90

Gain of ubiquitination at K115 (P = 0.0516);Gain of ubiquitination at K115 (P = 0.0516);Gain of ubiquitination at K115 (P = 0.0516);

MVP

1.0

ClinPred

0.97

GERP RS

5.9

Varity_R

0.90

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over