chr10-88941310-G-A

Position:

• chr10-88941310-G-A

Variant summary

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

The ENST00000224784.10(ACTA2):​c.535C>T​(p.Arg179Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R179L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA2 ENST00000224784.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.56

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]

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 chr10-88941309-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.976
• PP5: Variant 10-88941310-G-A is Pathogenic according to our data. Variant chr10-88941310-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88941310-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.535C>T	p.Arg179Cys	missense_variant	6/9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.535C>T	p.Arg179Cys	missense_variant	6/9	1	NM_001613.4	ENSP00000224784	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multisystemic smooth muscle dysfunction syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 08, 2024	- -
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 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) 0301 - Variant is absent from gnomAD (both v2 and v3). (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) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Alternative changes to leucine, histidine and serine have been reported in individuals with smooth muscle dysfunction syndrome (ClinVar, PMID: 29300374). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant in individuals with multisystemic smooth muscle dysfunction syndrome (ClinVar, PMID: 23613326, PMID: 29300374). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Nov 21, 2019	The p.Arg179Cys variant has been previously reported as de novo in patients with multisystemic smooth muscle dysfunction syndrome (MSMDS) disorder (PMID: 23613326, 27567161, 27244053, 27481187, 29875232). Multiple missense alterations at the same amino acid residue, including the recurrent p.Arg179His substitution, have been reported in association with MSMDS (PMID: 22831780, 24621862, 20734336, 26034244, 22752479, 24998021, 22946110, 24293535). Functional in-vitro studies variant using a baculovirus/insect cell system showed the p.Arg179Cys variant severely affects smooth muscle alpha-actin functions (PMID: 26153420). The p.Arg179Cys variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In silico analyses support a deleterious effect of the p.Arg179Cys variant on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.535C>T (p.Arg179Cys) variant is classified as Pathogenic. -

Familial aortopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 20, 2018

Variant summary: ACTA2 c.535C>T (p.Arg179Cys) results in a non-conservative amino acid change in the encoded protein sequence indicated to be located near a key protein-protein interaction site (Moreno_2016). Five of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally asssessed. The variant was absent in 121348 control chromosomes (ExAC). Multiple publications have cited the variant in affected individuals presenting with a multisystemic smooth muscle dysfunction syndrome (MSMDS) and aortic event. Multiple studies indicate the variant was a de novo occurrence (Meuwissen_2012 and Moreno_2016). In addition, other variants affecting the same codon, Arg179His and Arg179Lys, have been reported in affected individuals indicating a potential mutational hot spot. One clinical diagnostic laboratory has submitted a clinical-significance assessments of "likely pathogenic" for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 2024

Identified in individuals with aortic aneurysms and multisystemic smooth muscle dysfunction syndrome referred for genetic testing at GeneDx in the published literature (PMID: 27481187, 23613326, 27567161, 27244053); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30300893, 27567161, 25759435, 27244053, 29300374, 24621862, 29875232, 33199432, 33342581, 34193752, 36909460, 35878552, 37886459, 27481187, 23613326) -

Aortic aneurysm, familial thoracic 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 05, 2022

This variant disrupts the p.Arg179 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20734336, 22752479, 22946110, 24293535, 24621862, 24998021, 26034244). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265026). This missense change has been observed in individual(s) with multisystemic smooth muscle dysfunction syndrome and childhood cardiovascular, autonomic and brain anomalies and aortic dissection or aneurysm (PMID: 23613326, 25759435, 27481187, 27567161). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 179 of the ACTA2 protein (p.Arg179Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.93
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.84		Gain of catalytic residue at L180 (P = 0.0093);
MVP		0.97
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.83
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

Other links and lift over

dbSNP: rs886039303; hg19: chr10-90701067; COSMIC: COSV56517476; COSMIC: COSV56517476;