ClinVar Miner

Submissions for variant NM_000432.3(MYL2):c.64G>A (p.Glu22Lys) (rs104894368)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000768488 SCV000203862 likely pathogenic Hypertrophic cardiomyopathy 2017-09-08 criteria provided, single submitter clinical testing The p.Glu22Lys variant in MYL2 has been reported in >20 individuals with HCM and segregated in >20 affected relatives (Alvarez-Acosta 2014, Claes 2015, Poetter 1996, Kabaeva 2002, LMM data). Most of these individuals were reported to have a dditional risk factors such as hypertension, suggesting reduced penetrance or th at this is a mild variant that may not cause disease on its own (Claes 2015). Th is variant did not segregate with disease in multiple affected relatives, though at least 3 of these individuals were reported to have hypertension or other ris k factors. This variant has also been identified in 2/33582 Latino and 2/111718 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b; dbSNP rs104894368). Multiple in vitro and transgenic animal s tudies have shown that the p.Glu22Lys variant impacts protein function (Levine 1 998, Roopnarine 2003, Szczesna 2001, Szczsna-Cordary 2004, Szczsna-Cordary 2007) . However, these assays may not accurately represent biological function. This v ariant was predicted to be pathogenic using a computational tool clinically vali dated by our laboratory. This tool's pathogenic prediction is estimated to be co rrect 94% of the time (Jordan 2011). In summary, the p.Glu22Lys variant is lik ely pathogenic; however, this variant may have a milder role or reduced penetran ce.
GeneDx RCV000158914 SCV000208849 pathogenic not provided 2016-10-07 criteria provided, single submitter clinical testing The E22K pathogenic variant in the MYL2 gene has been reported in multiple unrelated individuals with HCM (Poetter K et al., 1996; Kabaeva Z et al., 2002; Alvarez-Acosta L et al., 2014; Claes et al., 2015). Furthermore, numerous affected relatives of these individuals were also found to harbor the E22K variant. Of note, not all relatives identified to have the variant in these studies developed disease, suggesting comparatively low penetrance. Furthermore, Claes et al. (2015) argued that E22K, in the absence of additional risk factors for hypertophy, may be insufficient to cause HCM in some carriers. Nonetheless, functional studies indicate E22K alters Ca2+ binding activity and the phosphorylation state of the protein, supporting a contributory role for this variant in disease (Szczesna D et al., 2001; Roopnarine O et al., 2003). This aligns with in silico analysis, which predicts this variant is probably damaging to the protein structure/function. The E22K variant was not observed with any significant frequency 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. Additionally, the E22K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species.
Center for Medical Genetics Ghent,University of Ghent RCV000015109 SCV000299269 likely pathogenic Familial hypertrophic cardiomyopathy 10 2016-07-15 criteria provided, single submitter clinical testing
Invitae RCV000015109 SCV000549155 pathogenic Familial hypertrophic cardiomyopathy 10 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 22 of the MYL2 protein (p.Glu22Lys). 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 (rs104894368, ExAC 0.009%). This variant has been reported to segregate with hypertrophic cardiomyopathy in several families (PMID: 8673105, 12404107, 26497160, 27532257). ClinVar contains an entry for this variant (Variation ID: 14065). Experimental studies have shown that this missense change significantly affects calcium sensitivity of MYL2 ATPase activity and force development (PMID: 12668451, 14594949, 16076902, 17606808, 25324513, 26497160). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000015109 SCV000744074 pathogenic Familial hypertrophic cardiomyopathy 10 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000015109 SCV000745544 pathogenic Familial hypertrophic cardiomyopathy 10 2015-09-21 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000768488 SCV000886792 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000158914 SCV000927440 pathogenic not provided 2017-10-18 criteria provided, single submitter clinical testing
OMIM RCV000015109 SCV000035366 pathogenic Familial hypertrophic cardiomyopathy 10 2002-11-01 no assertion criteria provided literature only
Leiden Muscular Dystrophy (MYL2) RCV000015109 SCV000045755 not provided Familial hypertrophic cardiomyopathy 10 2012-03-26 no assertion provided curation
Forensic Genetics Laboratory,Harris County Institute of Forensic Sciences RCV000234985 SCV000263119 pathogenic Death in early adulthood 2015-03-27 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000015109 SCV000733135 pathogenic Familial hypertrophic cardiomyopathy 10 no assertion criteria provided clinical testing

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