Submissions for variant NM_000256.3(MYBPC3):c.3642G>A (p.Trp1214Ter) (rs368765949)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000206843	SCV000196741	likely pathogenic	Hypertrophic cardiomyopathy	2014-06-01	criteria provided, single submitter	research
GeneDx	RCV000158241	SCV000208176	pathogenic	not provided	2017-01-26	criteria provided, single submitter	clinical testing	The W1214X variant in the MYBPC3 gene has been reported in an Indian male patient with familial HCM who also harbored another variant in the MYH7 gene (Bashyam M et al., 2012). The variant was absent from 100 ethnically matched control individuals. W1214X is predicted to cause loss of normal protein function either by protein truncation or nonsense mediated mRNA decay. Other nonsense variants in the MYBPC3 gene have been reported in association with HCM. In summary, W1214X in the MYBPC3 gene is interpreted as a disease-causing variant.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201437	SCV000256182	likely pathogenic	Familial hypertrophic cardiomyopathy 4		criteria provided, single submitter	clinical testing
Invitae	RCV000206843	SCV000259243	pathogenic	Hypertrophic cardiomyopathy	2018-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1214*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. A different variant (c.3641G>A) giving rise to the same protein effect observed here (p.Trp1214*) has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21959974, 24093860), indicating that this residue may be critical for protein function. ClinVar contains an entry for this variant (Variation ID: 31800536). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Color	RCV001179298	SCV001343928	pathogenic	Cardiomyopathy	2019-08-20	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV001263457	SCV001441524	likely pathogenic	Primary dilated cardiomyopathy; Left ventricular noncompaction cardiomyopathy	2020-10-15	criteria provided, single submitter	clinical testing	We observed a c.3642G>A (p.W1214*) genetic variant in a 30-y.o. female proband, diagnosed with non-compaction cardiomyopathy, dilatation of cardiac chambers and heart rhythm disturbances. The proband also carried the additional variant of unknown clinical significance in MYBPC3 gene - p.P186L in heterozygous state. The family was unavailable for screening. The p.W1214* genetic variant is a nonsense mutation in the MYBPC3 gene. No functional studies are available for the p.W1214* variant, however, nonsense variants in MYBPC3 gene are well-known to cause cardiomyopathy through haploinsufficiency. According to Cardio Classifier predictions, mRNA carrying the p.W1214* variant, will be processed through nonsence-mediated decay mechanism, leading to haploinsufficiency. We assume that the p.W1214* variant could be classified as likely pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000158241	SCV001447398	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing