Submissions for variant NM_000256.3(MYBPC3):c.416C>G (p.Ser139Ter)

dbSNP: rs730880704

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158463	SCV000208398	likely pathogenic	not provided	2023-11-09	criteria provided, single submitter	clinical testing	Reported in individuals with HCM in published literature (PMID: 23233322, 26090888); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26090888, 23233322)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845352	SCV000987402	pathogenic	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Invitae	RCV001850214	SCV002137502	pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser139*) 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 individuals with hypertrophic cardiomyopathy (PMID: 23233322). ClinVar contains an entry for this variant (Variation ID: 181138). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002326899	SCV002630488	pathogenic	Cardiovascular phenotype	2020-09-22	criteria provided, single submitter	clinical testing	The p.S139* pathogenic mutation (also known as c.416C>G), located in coding exon 4 of the MYBPC3 gene, results from a C to G substitution at nucleotide position 416. This changes the amino acid from a serine to a stop codon within coding exon 4. This mutation has been detected in individuals with hypertrophic cardiomyopathy (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80; Liu X et al. Sci Rep, 2015 Jun;5:11411). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149963	SCV003837603	pathogenic	Cardiomyopathy	2021-10-27	criteria provided, single submitter	clinical testing