15-34793398-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2PP3_StrongPP5_Very_Strong

The NM_005159.5(ACTC1):c.301G>A(p.Glu101Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ACTC1
NM_005159.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 7.91

Variant links:

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]

ACTC1 links:

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

GJD2-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

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, 0.987

PP5

Variant 15-34793398-C-T is Pathogenic according to our data. Variant chr15-34793398-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34793398-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTC1	NM_005159.5 link	c.301G>A	p.Glu101Lys	missense_variant	Exon 3 of 7	ENST00000290378.6	NP_005150.1	P68032B3KPP5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6 link	c.301G>A	p.Glu101Lys	missense_variant	Exon 3 of 7	1	NM_005159.5	ENSP00000290378.4		P68032

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251492

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Aug 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect resulting in a decrease in sarcomeric force generation (Bookwater et al., 2006; Monserrat et al., 2007; Chow et al., 2014); 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: 19799913, 21622575, 16267253, 30392975, 30847666, 24736382, 17611253, 16611632, 24510615, 26715934, 21551322, 27532257, 18506004, 26109583, 31397097, 31481237, 26061005, 10966831, 34540771, 33500567, 33673806) -

Mar 07, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 18, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACTC1: PP1:Strong, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting -

Hypertrophic cardiomyopathy 11

Pathogenic:4

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP2+PS4_Moderate+PP1_Strong+PS3_Supporting+PP4 -

Sep 21, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000189243 /PMID: 7481775 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Dilated cardiomyopathy 1R

Pathogenic:2

Aug 19, 2020

Clinical Genetics Laboratory, Region Ostergotland

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM2, PP1, PP3, PP5 -

Dec 19, 2024

Pediatrics/Division of Genetics and Metabolism, University of Kentucky

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vivo

The NM_005159.4 c.301G>A (p.Glu101Lys) is a missense variant. This variant is located in a mutational hot spot region (PM1). Missense variants are a common disease mechanism for this gene (PP2), and multiple lines of computational evidence support a deleterious effect (PP3). The variant has been previously reported as pathogenic (clinVar id# 18331). In the crystal structure of the actin monomer, this substitution is located on the surface of Sub-domain 1. The charge reversal caused by Glu101Lys substitution could destabilize the N-terminal domain of the ACTC1. Alternatively, the charge reversal could affect ACTC1 interactions with partner proteins. In summary, this variant meets the criteria to be classified as pathogenic based on the ACMG/AMP criteria applied. -

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

Pathogenic:2

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 101 of the ACTC1 protein (p.Glu101Lys). This variant is present in population databases (rs193922680, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM), apical HCM or left ventricular noncompaction (PMID: 10966831, 17611253, 18506004). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Glu99Lys, or E99K,. ClinVar contains an entry for this variant (Variation ID: 18331). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTC1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACTC1 function (PMID: 16611632, 19799913, 21622575). For these reasons, this variant has been classified as Pathogenic. -

Jul 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Pathogenic:1

May 06, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Left ventricular noncompaction 4

Pathogenic:1

Jun 03, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Aug 18, 2011

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Jul 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu101Lys variant in ACTC1 has been reported in 8 families with HCM, apica l HCM or LVNC, segregated with disease in >10 affected individuals, and was abse nt from 500 control chromosomes (also reported as Glu99Lys; Olson 2000, Arad 200 5, Monserrat 2007, Klaassen 2008). This variant has been identified in 1/66730 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs193922680). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants m ay be present at a low frequency in the general population. In vitro studies ind icate that this variant leads to reduced affinity of myosin for actin and result s in decreased force generation (Bookwalter 2006, Debold 2010, Chow 2014). Furth ermore, a mouse model harboring this variant presented with hypertrophic cardiom yopathy and had a decreased lifespan (Song 2011). In summary, the p.Glu101Lys va riant meets our criteria for pathogenicity (www.partners.org/personalizedmedicin e/lmm) based on segregation studies and functional evidence. -

Cardiovascular phenotype

Pathogenic:1

Nov 15, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E101K pathogenic mutation (also known as c.301G>A), located in coding exon 2 of the ACTC1 gene, results from a G to A substitution at nucleotide position 301. The glutamic acid at codon 101 is replaced by lysine, an amino acid with similar properties. This mutation (also referred to as E99K in the literature) was first reported in a family with hypertrophic cardiomyopathy (HCM) in which seven affected individuals were found to be carriers (Olson TM et al. J. Mol. Cell. Cardiol., 2000 Sep;32:1687-94). This mutation was subsequently reported to segregate with disease in several additional families with HCM or left ventricular non-compaction (LVNC) (Arad M et al. Circulation, 2005 Nov;112:2805-11; Monserrat L et al. Eur. Heart J., 2007 Aug;28:1953-61; Klaassen S et al. Circulation, 2008 Jun;117:2893-901). Functional studies have reported this mutation to result in slower motility, reduced average force, and a weakened interaction with cardiac myosin in the presence of ATP (Bookwalter CS et al. J. Biol. Chem., 2006 Jun;281:16777-84). In addition, transgenic mice expressing p.E101K were reported to have similar features of HCM as those seen in patients with this mutation (Song W et al. J. Biol. Chem., 2011 Aug;286:27582-93). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.87

Sift4G

Uncertain

0.036

Polyphen

0.79

Vest4

0.90

MutPred

0.94

Gain of methylation at E101 (P = 0.0049);

MVP

0.99

MPC

3.1

ClinPred

0.95

GERP RS

5.6

Varity_R

0.81

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over