Submissions for variant NM_000256.3(MYBPC3):c.1120C>T (p.Gln374Ter)

dbSNP: rs730880635

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158333	SCV000208268	pathogenic	not provided	2012-03-12	criteria provided, single submitter	clinical testing	p.Gln374Stop (Q374X) at the protein level and c.1120 C>T at the cDNA level. The Gln374Stop mutation in the MYBPC3 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism. Gln374Stop is predicted to cause loss of normal protein function either through protein truncation or absence of protein product due to nonsense mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. Gln374Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845491	SCV000987589	pathogenic	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Invitae	RCV001381872	SCV001580439	pathogenic	Hypertrophic cardiomyopathy	2023-04-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 181061). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27483260, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln374*) 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).