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

dbSNP: rs730880635

Total submissions: 4

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381872	SCV001580439	pathogenic	Hypertrophic cardiomyopathy	2024-11-16	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27483260, 27532257). ClinVar contains an entry for this variant (Variation ID: 181061). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786424	SCV005399463	pathogenic	Hypertrophic cardiomyopathy 4	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic and observed in individuals with hypertrophic cardiomyopathy (HCM; DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in at least five unrelated individuals with HCM (ClinVar, cardiodb.org, PMID: 34601892, PMID: 27483260). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign