rs121434527

chr10-88939542-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001613.4(ACTA2):c.773G>A(p.Arg258His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.91

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

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-88939543-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, ACTA2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 10-88939542-C-T is Pathogenic according to our data. Variant chr10-88939542-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA2	NM_001613.4	c.773G>A	p.Arg258His	missense_variant	7/9	ENST00000224784.10
ACTA2-AS1	NR_125373.1	n.1611C>T		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA2	ENST00000224784.10	c.773G>A	p.Arg258His	missense_variant	7/9	1	NM_001613.4	P1
ACTA2-AS1	ENST00000437930.4	n.1652C>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 09, 2016	The patient had genetic testing which included sequencing of 22 genes associated with aneurysms and dissections and related conditions: ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MED12, MYH11, MYLK, NOTCH1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, SMAD6, TGFB2, TGFB3, TGFBR1 and TGFBR2. Results reported on November 1, 2016 show that a variant was found: p.Arg258His (c.773G>A) the ACTA2 gene. p.Arg258His (c.773G>A) in the ACTA2 gene (NM_001613.2) The lab classifies this variant as likely pathogenic. Given case data and lack of the variant in the general population we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in multiple unrelated cases of aneurysm, dissection and stroke (not including this patient's family). There is strong segregation data in the family listed in the Guo et al paper. R258H been observed in multiple unrelated individuals referred for Marfan/TAAD testing at GeneDx, and in one family, R258H was presumed de novo in an affected proband following negative parental testing. Guo, et al 2009 (PMID: 19409525) reported this variant in a family from their Texas cohort as summarized in the figure below. Two other families also had missense variation at this position p.Arg258Cys. In these families, 10 out of 14 mutation carriers had aortic disease and seven had onset of strokes at ages ranging from 5 to 46 years of age. Five of seven acute strokes were classified as Moyamoya disease, a rare cerebral arteriopathy caused by occlusion of the supraclinoid portion of the internal carotid arteries as a result of fibrocellular proliferation in the arteries (Figure S2A). The other two individuals, TAA377:II:1 and III:2, had strokes at ages 32 and 17 years, respectively, but imaging records could not be obtained. Recent imaging studies identified fusiform cerebral aneurysms in both individuals (current ages 53 and 27 years [Figure S2B]). They conclude that p.R258C/H mutations are associated primarily with strokes, including those with an age at onset less than 20 years, and not with CAD. Analysis of the p.R258C/H mutations indicates that these mutations result in a 6.51-fold increased risk of stroke (CI:1.71–24.72, p value = 0.02). Regalado, et al., 2015 reported P.R258H and p.R258C in their cohort. They merged the two conditions together. Patients with a p.R258 had a cumulative risk of aortic event of 0.90 (95% CI, 0.68–0.99) by age 63 years. Using Cox regression analysis with correction for intrafamilial correlation, we found that individuals who carry mutations disrupting p.R179 (hazard ratio [HR], 26.39; 95% CI, 10.40–66.95) and p.R258 (HR, 2.05; 95% CI, 1.17–3.58) experienced significantly more aortic events than those with other ACTA2 mutations. These findings remained significant after adjustment for sex and race except for p.R258 substitutions. However, analysis without the individuals with p.R179 substitutions showed a significant HR for p.R258 (HR, 2.02; 95% CI, 1.03–3.95; P=0.041) compared with other mutations. The p.R258C/H mutations lie within the SM a-actin SD4 domain (Figure 2B). This domain participates in the opening and closing of the nucleotide binding cleft (per Guo, et al 2009). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.978). The argenine at codon 258 is conserved across species. As reported in the literature, other variants have been reported in association with disease at this codon (p.R258C). There is no variation at codon 258, or neighboring amino acids (257-263) listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2018	The R258H pathogenic variant in the ACTA2 gene has been reported previously in five individuals from one familywith a history of TAAD, Moyamoya disease (a distinctive pattern of occlusive stroke), and early onset stroke (<20years); however, one of the five variant carriers was a clinically unaffected young adult at the time of publication (Guoet al., 2007; Guo et al., 2009). Subsequently, Regalado et al (2015) studied a group of 277 individuals harboring 41different ACTA2 variants and found that variants disrupting amino acid residue R258 (R258C and R258H) wereassociated with a significantly increased risk for aortic events at younger ages compared to all other variants studied.In addition, R258H been observed in multiple unrelated individuals referred for Marfan/TAAD testing at GeneDx,and in one family, R258H was presumed de novo in an affected proband following negative parental testing.Furthermore, R258H was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations.Although the R258H variant is a conservative amino acid substitution, it occurs at a position that is conserved acrossspecies. Moreover, in vitro functional studies showed that R258H alters actin filament conformation and stability(Guo et al., 2007; Malloy L et al., 2012). Additionally, another missense variant in the same residue (R258C) hasbeen reported in the Human Gene Mutation Database in association with TAAD (Stenson et al., 2014), furthersupporting the functional importance of this residue.In summary, R258H in the ACTA2 gene is interpreted as a pathogenic variant. -

Aortic aneurysm, familial thoracic 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 14, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg258 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17994018, 19409525, 26153420). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ACTA2 function (PMID: 22753406). 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. ClinVar contains an entry for this variant (Variation ID: 18277). This missense change has been observed in individuals with thoracic aortic disease (PMID: 19409525, 25759435). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the ACTA2 protein (p.Arg258His). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2023

The p.R258H variant (also known as c.773G>A), located in coding exon 6 of the ACTA2 gene, results from a G to A substitution at nucleotide position 773. The arginine at codon 258 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with thoracic aortic aneurysm and dissection (TAAD), including segregating with disease in two families and a de novo occurrence in one individual (Guo DC et al. Nat Genet, 2007 Dec;39:1488-93; Kathiravel U et al. Mol Cell Probes, 2013 Apr;27:103-8; Yang H et al. Sci Rep, 2016 Sep;6:33002; Diness BR et al. J Neurol Sci, 2020 Aug;415:116897; Zeng Y et al. Front Cardiovasc Med, 2022 Nov;9:1030160). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Moyamoya disease 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.95
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.94		Loss of catalytic residue at R258 (P = 0.0436);
MVP		0.99
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.79
gMVP		0.88

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

Other links and lift over

dbSNP: rs121434527; hg19: chr10-90699299;