Submissions for variant NM_000256.3(MYBPC3):c.821+5G>A

dbSNP: rs397516077

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000768466	SCV000059323	likely pathogenic	Hypertrophic cardiomyopathy	2014-06-19	criteria provided, single submitter	clinical testing	The 821+5G>A variant in MYBPC3 has been reported in 2 individuals with HCM, was absent from 400 control chromosomes, and segregated with disease in 4 affected r elatives from 1 family (Carrier 1997, Richard 2003). In addition, this variant h as been identified by our laboratory in 2 Caucasian adults with HCM. This varian t is located in the 5' splice region and in vitro studies indicate this variant leads to aberrant splicing which is predicted to result in a truncated or absent protein (Carrier 1997, Flavigny 1999, Flavigny 2003). In summary, segregation a nd in vitro studies suggest that this variant is likely pathogenic, though addit ional studies are required to fully establish its clinical significance.
Center for Medical Genetics Ghent, University of Ghent	RCV000009138	SCV000299247	likely pathogenic	Hypertrophic cardiomyopathy 4	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000598548	SCV000709898	pathogenic	not provided	2021-01-07	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Published functional studies demonstrate that this variant leads to exon skipping and premature truncation (Carrier et al., 1997; Flavigny et al., 1999; Ito et al., 2017); Reported in ClinVar (ClinVar Variant ID# 42796; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31513939, 24721642, 28679633, 10610770, 9048664, 20624503, 12707239, 14613868, 30847666, 33673806)
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000009138	SCV000744865	uncertain significance	Hypertrophic cardiomyopathy 4	2017-09-14	criteria provided, single submitter	clinical testing
Center for Human Genetics, University of Leuven	RCV000768466	SCV000886748	pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770376	SCV000901817	likely pathogenic	Cardiomyopathy	2017-02-02	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000598548	SCV000927327	pathogenic	not provided	2017-07-04	criteria provided, single submitter	clinical testing
Invitae	RCV000768466	SCV001414711	pathogenic	Hypertrophic cardiomyopathy	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 9048664, 12707239, 23140321). This variant is also known as IVS7+5G>A. ClinVar contains an entry for this variant (Variation ID: 42796). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7 and introduces a premature termination codon (PMID: 9048664). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000009138	SCV002577578	likely pathogenic	Hypertrophic cardiomyopathy 4	2022-05-16	criteria provided, single submitter	clinical testing	PM2, PP3, PP5
OMIM	RCV000009138	SCV000029355	pathogenic	Hypertrophic cardiomyopathy 4	1997-03-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000598548	SCV001922902	uncertain significance	not provided		no assertion criteria provided	clinical testing