ClinVar Miner

Submissions for variant NM_000432.4(MYL2):c.37G>A (p.Ala13Thr) (rs104894363)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000626337 SCV000054783 benign Hypertrophic cardiomyopathy 2018-04-05 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036401 SCV000060056 uncertain significance not specified 2016-09-21 criteria provided, single submitter clinical testing The p.Ala13Thr variant in MYL2 has been reported in 6 individuals with HCM and s egregated with disease in 3 affected relatives from 2 families (Poetter 1996, An dersen 2001, Hougs 2005, Klaassen 2008, Mook 2013, LMM data). However, 2 additio nal relatives with cardiomyopathy from 2 families did not carry the p.Ala13Thr v ariant (2 non-segregations; Andersen 2001, LMM data). It has also been identifie d in 0.05% (34/66444) of European chromosomes by the Exome Aggregation Consortiu m (ExAC,; dbSNP rs104894363). Functional studies examining effects of this mutation on protein function were not conclusive (Szcz esna 2001, Szczesna-Cordary 2004, Farman 2014). Transgenic mice with the p.Ala13 Thr variant have left ventricular hypertrophy (Kazmierczak 2012). However, this study may not accurately represent biological function. In summary, due to confl icting information, the clinical significance of the p.Ala13Thr variant is uncer tain.
GeneDx RCV000766474 SCV000208846 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing The A13T variant of uncertain significance in the MYL2 gene has been reported previously in families with cardiac structural changes (Poetter et al., 1996; Anderson et al., 2001; Hougs et al., 2005; Li et al., 2017). Poetter et al. (1996) identified this variant in a patient presenting with pronounced mid left ventricular chamber thickening (MVH). The authors indicated that preliminary investigation of other family members suggested variable expression and decreased penetrance of the cardiac disease associated with this variant. Andersen et al. (2001) reported the A13T variant in three individuals in a Danish family. Two individuals (except a 10 year-old child) fulfilled diagnostic criteria for HCM; however, none of the individuals presented with mid-ventricular hypertrophy as described by Poetter et al. (1996). Hougs et al. (2005) reported A13T in a Danish proband with HCM who also harbored a variant in the MYH7 gene; familial segregation data suggested that either variant alone may cause HCM, but when inherited together result in a more severe phenotype. Similarly, the A13T variant was identified in two siblings with severe HCM who each harbored additional variants in the TTN and ALPK3 genes (Li et al., 2017). The siblings' more mildly affected mother did not harbor A13T, while their father with severe aortic stenosis and an unaffected young male relative did (Li et al., 2017).Ball et al. (2012) identified the A13T variant in a healthy 56-year-old male volunteer. Ball et al. (2012) also reported an HCM pedigree in which one affected individual carried the A13T variant, but the other affected individual did not, thus weakening the familial evidence that A13T is pathogenic. This variant has been identified independently and/or in conjunction with additional cardiogenetic variants in multiple individuals referred for cardiomyopathy genetic testing at GeneDx. Yet in one family, A13T did not segregate with HCM phenotype in one affected relative. Moreover, the A13T variant is observed in 54/10142 (0.5%) alleles from individuals of Ashkenazi Jewish ancestry and in 28/126678 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The A13T 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, this substitution is located in close proximity to the phosphorylation site of the protein (S15) (Poetter et al., 1996; Szczesna et al., 2001). Functional studies suggest that the A13T variant decreases calcium sensitivity, and mouse models of A13T show abnormal modelling of the heart and abnormal cross-bridge functions (Szczesna et al., 2001; Roopnarine et al., 2003; Szczesna-Cordary et al., 2004; Kazmierczak et al., 2012; Nagwekar et al., 2015).
Invitae RCV000015108 SCV000284831 likely benign Familial hypertrophic cardiomyopathy 10 2020-12-04 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000015108 SCV000493772 uncertain significance Familial hypertrophic cardiomyopathy 10 2016-01-27 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584799 SCV000692505 likely benign Familial hypertrophic cardiomyopathy 1 2017-08-29 criteria provided, single submitter research The MYL2 Ala13Thr variant has been identified in multiple unrelated cases of HCM (see references) and was absent in over 350 normal chromosomes (Poetter et al., 1996; Anderson et al., 2001). It is also observed in the Exome Aggregation Consortium dataset ( with an allele frequency of 0.03% (37 alleles). Evidence of MYL2 Ala13Thr segregation with disease has been weak. Li et al, (2017) describes a HCM family consisting of 3 affected family members, 3 variants were identified in the proband, including MYL2 Ala13Thr, but unlike the other 2 variants, it did not segregate to all 3 affected. Anderson et al. (2001) observed this variant in one HCM family: 3 carriers (2 affected, 1 clinically unaffected 10yr-old); 1 genotype-negative individual had left ventricular hypertrophy which may be due to hypertension and obesity. The disease in this same family was later suspected to be due to another variant (MYH7 Asn1327Lys) but this did not segregate in 1 clinically affected individual who met diagnostic criteria for HCM (Hougs et al., 2004). Additionally, MYL2 Ala13Thr was found not to segregate with disease in an additional HCM family identified by LMM, they harboured an MYBPC3 variant (Ball et al., 2012). Further, it failed to segregate in one LVNC family (Klassen S, et al., 2008). Two of the HCM families described above were Ashekenazi Jewish (Anderson et al., 2001; Ball et al., 2012), interestingly genome screening in 44 Ashkenazi Jewish centenarians identified MYL2 A13T in 2 people over the age of 94yrs, suggesting that this variant is a common polymorphism in this sub-population (Fraundenberg-Hua Y, et al., 2014). Functional studies including cell models suggest that MYL2 Ala13Thr may alter contractile function (Szczesna-Cordary D, et al., 2001; Roopnarine O, 2003; Szczesna-Cordary et al., 2004) and actin filament velocity (Farman GP, et al., 2014) in cardiac cells. A transgenic mouse model published by Kazmierczak et al., (2012) showed abnormal remodelling of the heart. However, it is noted that these studies may not accurately represent the biological system, in fact the amino acid at this position is not conserved in rats or mice. We have identified the MYL2 Ala13Thr variant in 2 HCM probands, both of North West European descent. Neither proband has a family history of HCM or sudden cardiac death. We note that additional variants have been identified in one proband which may contribute to the disease phenotype (MYH7 Asp1652Tyr; DSG2 Asp535Glu). Although there is reasonable supportive evidence for the pathogenicty of MYL2 Ala13Thr, based on the lack of segregation reported and a population frequency greater 0.02%, we classify this variant as "likely benign".
Ambry Genetics RCV000620870 SCV000740137 likely benign Cardiovascular phenotype 2020-09-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000148714 SCV000740463 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-06-20 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000015108 SCV000883093 uncertain significance Familial hypertrophic cardiomyopathy 10 2018-11-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778905 SCV000915313 likely pathogenic MYL2-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The MYL2 c.37G>A (p.Ala13Thr) missense variant has been reported in eight studies in which it is found in a heterozygous state in a total of 12 individuals, including six individuals affected with hypertrophic cardiomyopathy, two individuals affected with left ventricular noncompaction, three unaffected individuals, and one individual of unknown phenotype (Poetter et al. 1996; Andersen et al 2001; Ball et al. 2012; Jensen et al. 2013; Mook et al. 2013; Berge et al. 2014; Freudenberg-Hua et al. 2014; Klassen et al. 2014). The p.Ala13Thr variant was absent from 1020 control chromosomes but is reported at a frequency of 0.00070 in the European American population of the Exome Sequencing Project and is present in a homozygous state in one individual in the Exome Aggregation Consortium. In vitro studies were conducted to determine the effect of the p.Ala13Thr variant on the structure and Ca2+ binding affinity of the protein (Szczesna et al. 2001). It was found that the Ca2+ binding affinity was decreased by three-fold in the variant versus wild type. However, phosphorylation of the variant increased Ca2+ binding affinity over the phosphorylated wild type protein by 15-fold. Structural analysis showed an increase in alpha-helices from 18% to 29%. The authors suggest these changes in structure potentially interfere with physiological function of the protein. Farman et al. (2014) found the actin sliding velocity of the p.Ala13Thr variant to be significantly reduced, caused by an increased duty cycle when compared to wild type. Based on the evidence, the p.Ala13Thr variant is classified as likely pathogenic for MYL2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766474 SCV001148830 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV001184984 SCV001351096 benign Cardiomyopathy 2018-11-16 criteria provided, single submitter clinical testing
OMIM RCV000015108 SCV000035365 pathogenic Familial hypertrophic cardiomyopathy 10 1996-05-01 no assertion criteria provided literature only
Leiden Muscular Dystrophy (MYL2) RCV000015108 SCV000045753 not provided Familial hypertrophic cardiomyopathy 10 2012-03-26 no assertion provided curation
CSER _CC_NCGL, University of Washington RCV000148714 SCV000190444 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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