Submissions for variant NM_005159.5(ACTC1):c.301G>A (p.Glu101Lys)

gnomAD frequency: 0.00001  dbSNP: rs193922680

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029295	SCV000051941	pathogenic	Primary familial hypertrophic cardiomyopathy	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844601	SCV000061995	pathogenic	Hypertrophic cardiomyopathy	2016-07-21	criteria provided, single submitter	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.
GeneDx	RCV000157780	SCV000207710	pathogenic	not provided	2022-08-17	criteria provided, single submitter	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)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000019996	SCV000256188	likely pathogenic	Hypertrophic cardiomyopathy 11		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684792	SCV000260669	pathogenic	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2025-01-12	criteria provided, single submitter	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769471	SCV000900866	pathogenic	Cardiomyopathy	2016-05-06	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157780	SCV000927573	pathogenic	not provided	2018-03-07	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Region Ostergotland	RCV001807736	SCV002056145	likely pathogenic	Dilated cardiomyopathy 1R	2020-08-19	criteria provided, single submitter	clinical testing	PS4, PM2, PP1, PP3, PP5
3billion	RCV000019996	SCV002573215	pathogenic	Hypertrophic cardiomyopathy 11	2023-09-21	criteria provided, single submitter	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.
Ambry Genetics	RCV002433462	SCV002754279	pathogenic	Cardiovascular phenotype	2023-11-15	criteria provided, single submitter	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.
Fulgent Genetics, Fulgent Genetics	RCV000684792	SCV002811461	pathogenic	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2021-07-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000157780	SCV004010351	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ACTC1: PP1:Strong, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000157780	SCV005199112	pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000019996	SCV005416396	pathogenic	Hypertrophic cardiomyopathy 11		criteria provided, single submitter	clinical testing	PM2_Supporting+PP2+PS4_Moderate+PP1_Strong+PS3_Supporting+PP4
Pediatrics/Division of Genetics and Metabolism, University of Kentucky	RCV001807736	SCV005629072	pathogenic	Dilated cardiomyopathy 1R	2024-12-19	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000019996	SCV000040294	pathogenic	Hypertrophic cardiomyopathy 11	2008-06-03	no assertion criteria provided	literature only
OMIM	RCV000019997	SCV000040295	pathogenic	Left ventricular noncompaction 4	2008-06-03	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000157780	SCV001924825	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000157780	SCV001968715	pathogenic	not provided		no assertion criteria provided	clinical testing