Submissions for variant NM_000256.3(MYBPC3):c.3233G>A (p.Trp1078Ter)

dbSNP: rs397516006

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000533067	SCV000059215	pathogenic	Hypertrophic cardiomyopathy	2016-05-16	criteria provided, single submitter	clinical testing	The p.Trp1078X variant in MYBPC3 has been identified by our laboratory in 4 indi viduals with HCM. It has also been identified in 1/23606 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s397516006). This nonsense variant leads to a premature termination codon at pos ition 1078, which is predicted to lead to a truncated or absent protein. Heteroz ygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, the p.Trp1078X variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon i ts predicted impact to the protein.
Invitae	RCV000533067	SCV000623587	pathogenic	Hypertrophic cardiomyopathy	2023-09-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1078*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19574547, 25031304). ClinVar contains an entry for this variant (Variation ID: 42692). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198904	SCV001369899	pathogenic	Hypertrophic cardiomyopathy 4	2018-11-06	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP3,PP5.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798086	SCV002042197	pathogenic	Cardiomyopathy	2023-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444468	SCV002611736	pathogenic	Cardiovascular phenotype	2017-08-17	criteria provided, single submitter	clinical testing	The p.W1078* pathogenic mutation (also known as c.3233G>A), located in coding exon 30 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3233. This changes the amino acid from a tryptophan to a stop codon within coding exon 30. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) genetic testing cohort, as well as in myectomy samples from individuals with HCM (Helms AS et al. Circ Cardiovasc Genet, 2014 Aug;7:434-43; Helms AS et al. Circulation, 2016 Nov;134:1738-1748; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). 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.
GeneDx	RCV003226900	SCV003923348	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	Reported in association with HCM in the published literature (Helms et al., 2014; Walsh et al., 2017); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25031304, 27532257, 27535533)