rs121434528

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001613.4(ACTA2):c.772C>T(p.Arg258Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACTA2
NM_001613.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 10.0

Publications

32 publications found

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:

ACTA2-AS1 (HGNC:45169): (ACTA2 antisense RNA 1)

ACTA2-AS1 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 was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001613.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-88939542-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 18277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the ACTA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 4.6117 (above the threshold of 3.09). GenCC associations: The gene is linked to multisystemic smooth muscle dysfunction syndrome, connective tissue disorder, familial thoracic aortic aneurysm and aortic dissection, Moyamoya disease 5, aortic aneurysm, familial thoracic 6.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 10-88939543-G-A is Pathogenic according to our data. Variant chr10-88939543-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001613.4 link	c.772C>T	p.Arg258Cys	missense_variant	Exon 7 of 9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10 link	c.772C>T	p.Arg258Cys	missense_variant	Exon 7 of 9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111948

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000396

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:4

Jun 07, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.772C>T (p.Arg258Cys) variant of the ACTA2 gene replaces arginine with cysteine at codon 258. This sequence change has been reported in multiple individuals with thoracic aortic aneurysms and dissections (PMID 19409525, 25644172, 28652363, 33513575, 37042257, 36053285). This variant shows segregation within family members with incomplete penetrance (17994018). A confirmed de novo occurrence of this variant has been reported (PMID: 19409525). Experimental analysis of this variant in patient-specific smooth muscle cells demonstrated a detrimental impact on protein stability and contractile function (PMID 26153420). A detrimental impact on cytoskeletal functions using patient-specific fibroblasts has also been reported (PMID 28652363). Computational evidence suggests this variant is detrimental to ACTA2 protein function (REVEL score 0.932). The frequency of this variant in the general population database (gnomAD) is rare (0. 0.003%). Another variant disrupting the same amino acid has been interpreted as pathogenic (ClinVar ID: 18277). Clinvar contains an entry for this variant (Variation ID: 18278). Based on the available evidence, the c.772C>T (p.Arg258Cys) variant of the ACTA2 gene is classified as pathogenic. -

Mar 04, 2020

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R258C pathogenic mutation (also known as c.772C>T), located in coding exon 6 of the ACTA2 gene, results from a C to T substitution at nucleotide position 772. The arginine at codon 258 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was found to segregate with disease in two unrelated families with familial thoracic aortic aneurysms and dissections (TAAD) and premature ischemic strokes (Guo DC et al. Am J Hum Genet. 2009;84(5):617-27). This variant was also reported as de novo in one family with TAAD (Guo et al 2009). In addition, this variant very likely resulted from a de novo event in one family tested in our laboratory. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Sep 10, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with cysteine at codon 258 of the ACTA2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. An in vitro functional study has shown that this variant may decrease contractile function by altering interactions with myosin and tropomyosin (PMID: 26153420). Another functional study using dermal fibroblasts derived from carrier individuals has shown that this variant suppresses myofibroblast migration and contraction (PMID: 28652363). This variant has been reported in multiple unrelated individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 17994018, 19409525, 25644172, 25759435, 28652363, 30341550, 33513575, 36053285). It has been shown that this variant segregates with disease, including features of premature stroke and patent ductus arteriosus, in multiple affected individuals across two families (PMID: 17994018, 19409525). In one instance, this variant has been reported to occur as a de novo event (PMID: 33513575). This variant has been identified in 1/31384 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg258His, is considered to be disease-causing (ClinVar variation ID: 18277), suggesting that arginine at this position is important for ACTA2 protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Jun 06, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change in ACTA2 is predicted to replace arginine with cysteine at codon 258, p.(Arg258Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the SM alpha-actin SD4 domain (PMID: 19409525). There is a large physicochemical difference between arginine and cysteine. ACTA2, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1). This variant is present in a single individual from the European (non-Finnish) population in the population database gnomAD v2.1 (1/68,040 alleles), which is consistent with ACTA2-related disease. This variant has been reported in multiple probands with thoracic aortic aneurysm and aortic dissection (TAAD) with/without premature stroke, and segregates with disease in multiple families (PMID: 19409525, 25644172, 25759435, 37042257). The variant has also been identified as a de novo occurrence with confirmed parental relationships in one family with cerebral arteriopathy and mild TAAD and as a de novo occurrence with unconfirmed parental relationships in one individual with TAAD (PMID: 19409525, 33513575). This variant alters protein function in a dominant negative manner in both in vitro functional assays and patient fibroblasts (PMID: 26153420, 28652363). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.932). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4_Moderate, PS2_Moderate/PM6, PP1_Moderate, PP3_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP4. -

Aortic aneurysm, familial thoracic 6

Pathogenic:3

May 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the ACTA2 protein (p.Arg258Cys). This variant is present in population databases (rs121434528, gnomAD 0.007%). This missense change has been observed in individual(s) with nonsyndromic heritable thoracic aortic disorder and thoracic aortic aneurysms and patent ductus arteriosus (PMID: 17994018, 19409525, 25644172). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18278). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTA2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACTA2 function (PMID: 26153420). For these reasons, this variant has been classified as Pathogenic. -

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygote). (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 (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least 10 unrelated individuals with thoracic aortic disorders and has been classified as pathogenic (ClinVar, PMID:33513575, PMID:19409525, PMID:25644172, PMID:36053285). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Nov 17, 2017

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 18, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with premature stroke, PDA and TAAD in multiple unrelated probands and families (PMID: 25644172, 19409525, 25759435); Published functional studies demonstrate a damaging effect as this variant disrupts actin dynamics and leads to contractile dysfunction (PMID: 26153420, 28652363); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17994018, 33513575, 26934405, 27879251, 28652363, 30341550, 30300893, 28848449, 25759435, 36053285, 34498425, 35567597, 37587538, 32814715, 33990081, 34546411, 34600884, 30880160, 36194209, 32464348, 32997990, 33776470, 34062765, 25644172, 26153420, PetrovI2022[Article], 19409525) -

Moyamoya disease 5

Pathogenic:1

May 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

PhyloP100

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.93

Sift4G

Uncertain

0.021

Polyphen

1.0

Vest4

0.94

MutPred

0.92

Loss of catalytic residue at R258 (P = 0.039);

MVP

0.97

ClinPred

1.0

GERP RS

6.1

Varity_R

0.77

gMVP

0.94

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over