15-34792524-A-G

Variant names:

• chr15-34792524-A-G
• rs730880409
• NM_005159.5:c.500T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_005159.5(ACTC1):​c.500T>C​(p.Ile167Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 9.32

Genes affected

ACTC1 (HGNC:143): (actin alpha cardiac muscle 1) Actins are highly conserved proteins that are involved in various types of cell motility. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The protein encoded by this gene belongs to the actin family which is comprised of three main groups of actin isoforms, alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Defects in this gene have been associated with idiopathic dilated cardiomyopathy (IDC) and familial hypertrophic cardiomyopathy (FHC). [provided by RefSeq, Jul 2008]

GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ACTC1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 4.5244 (above the threshold of 3.09). Trascript score misZ: 6.3156 (above the threshold of 3.09). GenCC associations: The gene is linked to dilated cardiomyopathy, hypertrophic cardiomyopathy, atrial septal defect 5, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1R, hypertrophic cardiomyopathy 11.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTC1	NM_005159.5	c.500T>C	p.Ile167Thr	missense_variant	Exon 4 of 7	ENST00000290378.6	NP_005150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6	c.500T>C	p.Ile167Thr	missense_variant	Exon 4 of 7	1	NM_005159.5	ENSP00000290378.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 24, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. ACTC1 p.Ile167Thr Based on the data reviewed below, we consider this variant to be of uncertain significance. The variant is novel. As of December 28, 2011, no variation at codon 167 of ACTC1 has been reported in the literature (according to searches of PubMed and Google), in the Harvard Sarcomere Protein Gene Mutation Database, or in an ACTC1-specific mutation database curated by Johan den Dunnen and accessed through the Leiden Open Variation Database (http://www.dmd.nl/nmdb/home.php?select_db=ACTC1). Of note, pathogenic HCM variants have been reported at the two immediately adjacent amino acids: Pro166Ala (reported 2 times), and Tyr168Cys, which are present in the Harvard and Leiden databases with published references. This is a non-conservative amino acid substitution in which a nonpolar Isoleucine is replaced by a neutral, polar Threonine. The change is at a residue that is completely conserved across vertebrate species, as are the surrounding residues. In silico analysis with PolyPhen-2 predicts the variant to be benign. However, in silico analysis with SIFT and Mutation Taster predicts the variant to be disease-causing. GeneDx reports that the variant was absent in up to 100 presumably healthy individuals of Caucasian ancestry. The variant is not reported in the NHLBI Exome Sequencing Project data set (http://evs.gs.washington.edu/EVS/), dbSNP (www.ncbi.nlm.nih.gov/SNP), or 1000 Genomes (http://browser.1000genomes.org/index.html) as of December 28, 2011. The ACTC1 gene product (cardiac alpha-actin) has a 99% identical isoform (skeletal alpha-actin), coded by ACTA1. These two proteins differ by only 4 out of 375 amino acids. In fact, they have overlapping functions: During fetal development cardiac alpha-actin serves as the isoform in skeletal muscle, and mature heart muscle contains both cardiac alpha-actin (80% of the total) and skeletal alpha-actin (20% of the total). Given the extensive overlap in function and amino acid sequence, data about skeletal alpha-actin (ACTA1) variants can help guide our assessment of the patient’s cardiac alpha-actin (ACTC1) variant. Pathogenic mutations in ACTA1 cause congenital skeletal myopathies, and variants in this protein are catalogued in a locus-specific database created by the Laing Molecular Neurogenetics Laboratory at the Western Australian Institute for Medical Research (http://www.waimr.uwa.edu.au/research/lovd.html). The database contains no variants at Ile167. However, mutations at several nearby residues (within 10 residues to either side) are reported to cause congenital skeletal myopathies: Gly160Cys, His163Asp, His163Tyr (possibly recessive), Val165Leu (reported 3 times), Val165Met, Ala172Glu (reported 2 times), and Ala172Gly. -

Cardiomyopathy Uncertain:1

Mar 08, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Uncertain:1

Mar 06, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with threonine at codon 167 of the ACTC1 protein (p.Ile167Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ACTC1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Apr 27, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign in association with a ACTC1-related disorder to our knowledge; 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: 30681346) -

Cardiovascular phenotype Uncertain:1

Aug 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I167T variant (also known as c.500T>C), located in coding exon 3 of the ACTC1 gene, results from a T to C substitution at nucleotide position 500. The isoleucine at codon 167 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.9	H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.96
Sift4G	Pathogenic	0.0	D
Polyphen		0.12	B
Vest4		0.87
MutPred		0.85		Loss of stability (P = 0.0164);
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
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: rs730880409; hg19: chr15-35084725;