rs727504379

Variant names:

• chr15-34791238-A-G
• rs727504379
• NM_005159.5:c.866T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_005159.5(ACTC1):​c.866T>C​(p.Ile289Thr) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.51
• Publications: 1 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 15-34791238-A-G is Pathogenic according to our data. Variant chr15-34791238-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 177886.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
ACTC1	NM_005159.5	c.866T>C	p.Ile289Thr	missense_variant	Exon 6 of 7	ENST00000290378.6	NP_005150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6	c.866T>C	p.Ile289Thr	missense_variant	Exon 6 of 7	1	NM_005159.5	ENSP00000290378.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Sep 22, 2011

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change is denoted p.Ile289Thr (aka I289T) at the protein level, and c.866 T>C at the cDNA level. The Ile289Thr variant in the ACTC1 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Ile289Thr results in a non-conservative amino acid substitution of a non-polar Isoleucine with a neutral, polar Threonine at a position that is class conserved throughout evolution. In silico analysis predicts Ile289Thr is disease-causing. A mutation in a nearby codon (Ala297Ser) has been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Furthermore, Ile289Thr was not detected in up to 200 control alleles from individuals of Caucasian ancestry tested at GeneDx, indicating it is not a common benign variant in this population. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine the clinical significance of the Ile289Thr variant in the ACTC1 gene though evidence suggests it may be disease-causing. The variant is found in DCM panel(s). -

Primary dilated cardiomyopathy Pathogenic:1

Jul 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile289Thr variant in ACTC1 has been identified in 3 individuals with dilated cardiomyopathy (DCM), 2 of whom had additional cardiomyopathy features (1 with restrictive cardiomyopathy (RCM) associated with an atrial septal defects (ASDs) and 1 with left ventricular non-compaction (LVNC; Rodriguez-Serrano 2014 PMID: 25201647, GeneDx pers. comm., LMM data). This variant segregated with DCM in 1 affected relative (LMM data) and with LVNC in 3 affected relatives from another family, 1 of whom had additional clinical features such as ASDs (Rodriguez-Serrano 2014 PMID: 25201647). This variant has also been reported by clinical laboratories in ClinVar (Variation ID 177886) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Ile289Thr are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Ile289Thr variant is likely pathogenic for autosomal dominant cardiomyopathy, particularly DCM and LVNC. ACMG/AMP criteria applied: PS4_Supporting, PP1_Moderate, PM2, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
CardioboostCm	Uncertain	0.32
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.95
Sift4G	Uncertain	0.027	D
Polyphen		0.34	B
Vest4		0.83
MutPred		0.49		Gain of relative solvent accessibility (P = 0.005);
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.84
gMVP		0.93
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs727504379; hg19: chr15-35083439;