Submissions for variant NM_005159.5(ACTC1):c.301G>A (p.Glu101Lys) (rs193922680)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Integrated Genetics/Laboratory Corporation of America	RCV000029295	SCV000051941	pathogenic	Primary familial hypertrophic cardiomyopathy	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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	2018-05-21	criteria provided, single submitter	clinical testing	The E101K pathogenic variant in the ACTC1 gene was initially reported by Olson et al. (2000) in an individual with HCM (reported as Glu99Lys due to alternative nomenclature), and was found to segregate with an HCM phenotype in this family. Arad et al. (2005) subsequently identified the E101K variant in two families with a shared haplotype, suggesting a founder effect, and it consistently segregated with an apical hypertrophy phenotype. Additionally, Monserrat et al. (2007) reported E101K as a founder mutation in five families from Spain with multiple individuals exhibiting left ventricular non-compaction (LVNC) and HCM phenotypes. The clinical features associated with the E101K variant are variable, with some individuals experiencing a benign course while others were diagnosed after arrhythmic events (Monserrat et al., 2007). Furthermore, two unrelated probands with definitive LVNC have been reported to harbor this variant, both of whom inherited the variant from an affected parent (Klaassen et al., 2008; Probst et al., 2011).The E101K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). E101K results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine in a region of the actin filament close to the myosin head (Olson et al., 2000). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is damaging to protein structure/function. Various functional studies demonstrated that this variant results in a decrease in sarcomeric force generation (Bookwalter et al., 2006; Monserrat et al., 2007; Chow et al., 2014). Furthermore, a transgenic mouse model demonstrated that E101K causes higher myofibrillar calcium sensitivity, which is proposed to be responsible for the cardiac phenotype in humans and mice with this variant (Song et al., 2011).
Laboratory of Genetics and Molecular Cardiology,University of São Paulo	RCV000019996	SCV000256188	likely pathogenic	Familial hypertrophic cardiomyopathy 11		criteria provided, single submitter	clinical testing
Invitae	RCV000684792	SCV000260669	pathogenic	Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2018-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 101 of the ACTC1 protein (p.Glu101Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs193922680, <0.01%). This variant was reported individuals affected with hypertrophic cardiomyopathy (HCM), apical HCM or left ventricular noncompaction and has also been shown to segregate with disease in multigenerational families (PMID: 10966831, 17611253, 18506004). ClinVar contains an entry for this variant (Variation ID: 18331). This variant is also known as p.Glu99Lys, or E99K, in the literature. Experimental studies have shown that this missense change decreases the affinity of ACTC1 towards myosin and  increases the degree of thin filament mediated inhibition of myosin strong-binding, leading to a reduction in force generation and velocity  (PMID: 16611632, 19799913). In addition, transgenic mice expressing this variant reproduce many of the characteristics of hypertrophic cardiomyopathy seen in patients at the single filament and whole animal levels (PMID: 21622575). In summary, this variant has been reported in many affected families segregating with the disease and has been shown to affect protein function. 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
OMIM	RCV000019996	SCV000040294	pathogenic	Familial 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