Submissions for variant NM_000256.3(MYBPC3):c.1387C>T (p.Gln463Ter)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158080	SCV000208015	pathogenic	not provided	2013-02-08	criteria provided, single submitter	clinical testing	p.Gln463Stop (CAG>TAG): c.1387 C>T in exon 16 of the MYBPC3 gene (NM_000256.3) The Gln463Stop mutation in the MYBPC3 gene has been reported in association with HCM (Ma Z et al., 2009; Zou Y et al. 2013). Ma et al. reported Gln463Stop in one individual with HCM (reported as Asp463Stop). Subsequently, Zou Y et al. identified Gln463Stop in another individual with HCM. Gln463Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. In summary, Gln463Stop 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).
Ambry Genetics	RCV002390376	SCV002702623	pathogenic	Cardiovascular phenotype	2019-02-20	criteria provided, single submitter	clinical testing	The p.Q463* pathogenic mutation (also known as c.1387C>T), located in coding exon 16 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1387. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This mutation was detected in an individual with restrictive cardiomyopathy, as well as in her two similarly affected family members (Wu W et al. J Am Heart Assoc, 2015 Jul;4:[Epub ahead of print]). This variant has also been reported in an individual with hypertrophic cardiomyopathy, who also had an MYH7 variant detected (Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV002516377	SCV003440378	pathogenic	Hypertrophic cardiomyopathy	2022-11-09	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: 180933). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20021930, 23283745). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln463*) 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).

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