Submissions for variant NM_000256.3(MYBPC3):c.3258G>A (p.Trp1086Ter)

dbSNP: rs1595841552

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001007987	SCV001167719	pathogenic	not provided	2019-02-25	criteria provided, single submitter	clinical testing	The W1086X (c.3258 G>A) pathogenic variant in the MYBPC3 gene has been reported in association with hypertrophic cardiomyopathy (HCM) (Murphy et al., 2016). In addition, a different nucleotide substitution resulting in the same nonsense variant (c.3257 G>A) has also been reported in association with HCM (Lopes et al., 2015; Walsh et al., 2017). W1086X is is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Many other downstream nonsense variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the W1086X variant is not observed in large population cohorts (Lek et al., 2016).
Invitae	RCV003586261	SCV004294784	pathogenic	Hypertrophic cardiomyopathy	2023-08-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 816955). This premature translational stop signal has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 26914223). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1086*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547).