rs397517071

Variant names:

• chr15-34792092-A-G
• rs397517071
• NM_005159.5:c.806T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_005159.5(ACTC1):​c.806T>C​(p.Ile269Thr) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTC1 NM_005159.5 missense, splice_region
• Scores: Splicing: ADA: 0.002350
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 9.32
• Publications: 3 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: Likely_pathogenic. The variant received 6 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, 10 uncertain in NM_005159.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 15-34792092-A-G is Pathogenic according to our data. Variant chr15-34792092-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45190.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTC1	NM_005159.5	c.806T>C	p.Ile269Thr	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000290378.6	NP_005150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6	c.806T>C	p.Ile269Thr	missense_variant, splice_region_variant	Exon 5 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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Feb 11, 2014

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I269T variant in the ACTC1 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism to our knowledge, but this variant has been observed in other unrelated individuals tested for DCM I269T results in a non-conservative amino acid substitution of a non-polar Isoleucine with a neutral, polar Threonine. While the Ile269 residue is not uniformly conserved across species, variation is limited to other non-polar amino acids at this position. In silico analysis predicts I269T is damaging to the protein structure/function. Mutations in nearby residues (M271V, S273F) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Furthermore, I269T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, I269T is a good candidate for a disease-causing mutation. -

Mar 01, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM2, PS4_moderate -

Nov 20, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy;C1960469:Left ventricular noncompaction Pathogenic:1

Apr 27, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile269Thr variant has been identified in 3 individuals with early-onset ca rdiomyopathy and segregated with disease in 5 affected family members from 2 fam ilies (GeneDx pers. comm., LMM data). Phenotypes of these individuals included D CM, LVNC, and HCM. Severity in affected family members was variable raising the possibility that other genetic or environmental factors were present in the earl y onset cases. The p.Ile269Thr variant was absent from large population studies but has been reported in ClinVar (Variation ID# 45190). Computational prediction tools and conservation analysis suggest that the p.Ile269Thr variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, although additional studies are required to fully establi sh its clinical significance, the p.Ile269Thr variant is likely pathogenic. ACMG /AMP Criteria applied: PM2; PP1_Moderate; PP3; PS4_Supporting. -

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

May 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 45190). This missense change has been observed in individual(s) with clinical features of ACTC1-related conditions (PMID: 24503780). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 269 of the ACTC1 protein (p.Ile269Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
CardioboostCm	Uncertain	0.80
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.026	D
Polyphen		0.0070	B
Vest4		0.85
MutPred		0.57		Loss of stability (P = 0.0174);
MVP		0.99
MPC		1.9
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.86
gMVP		0.98
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.024
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

Other links and lift over

dbSNP: rs397517071; hg19: chr15-35084293;