NM_005159.5:c.301G>A

Variant names:

• chr15-34793398-C-T
• rs193922680
• NM_005159.5:c.301G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 14P and 4B. PM1 PP3_Strong PP5_Very_Strong BS2

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. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E101G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 7.91
• Publications: 36 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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_005159.5
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 18331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

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)

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

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 07, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Jun 03, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 26, 2024

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 v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.87 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000018331 /PMID: 10966831 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16267253, 18506004, 21551322, 26061005, 26715934, 27532257, 30847666, 31397097, 33500567, 33673806, 34540771). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Dilated cardiomyopathy 1R Pathogenic:3

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.

Jul 23, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 7 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar and has been reported in individuals with hypertrophic cardiomyopathy (cardiodb.org) and left ventricular non-compaction (VCGS internal data). In addition, it has also been reported in the literature in association with a multisystemic syndrome with a predominant cardiac phenotype that can overlap with Noonan syndrome (PMID: 40421724); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from glutamic acid to lysine; This variant is heterozygous; This gene is associated with autosomal dominant disease; Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 1 heterozygote(s), 0 homozygote(s)); Variant is located in the annotated actin domain (DECIPHER); The mechanism of disease for this gene is not clearly established. Missense variants have been described with both loss and gain of function properties (PMID: 29719515). However, the exact mechanism remains unclear; This variant has been shown to be paternally inherited by trio analysis.

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	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D
Sift4G	Uncertain	0.036	D
Vest4		0.90
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.93
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193922680; hg19: chr15-35085599; COSMIC: COSV51758448; COSMIC: COSV51758448;