Submissions for variant NM_000256.3(MYBPC3):c.1224-19G>A

dbSNP: rs587776699

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000168768	SCV000170461	likely pathogenic	not specified	2018-12-18	criteria provided, single submitter	clinical testing	The c.1224-19G>A likely pathogenic variant in the MYBPC3 gene has been reported in association with hypertrophic cardiomyopathy (Waldmuller et al., 2008; Frank-Hansen et al., 2008; Mendes de Almeida et al., 2017). Additionally, functional studies using mRNA analysis demonstrate that this variant creates a splice acceptor site upstream of the canonical splice acceptor site and adds 17 nucleotides to the transcript (Frank-Hansen et al., 2008). This variant is predicted to result in aberrant gene splicing that leads to protein truncation and frameshift (Frank-Hansen et al., 2018). Furthermore, other deep intronic splice site variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.1224-19 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, c.1224-19G>A in the MYBPC3 gene is interpreted as a likely pathogenic variant.
Invitae	RCV000467263	SCV000546477	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 13 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 present in population databases (rs587776699, gnomAD 0.02%). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18258667, 18337725, 30645170, 33673806, 34400558). ClinVar contains an entry for this variant (Variation ID: 138326). Studies have shown that this variant results in extension of the transcript by 17 nucleotides and introduces a premature termination codon (PMID: 18337725). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics	RCV000788553	SCV000927706	likely pathogenic	not provided	2018-05-24	criteria provided, single submitter	clinical testing
3billion	RCV000009149	SCV002521736	pathogenic	Hypertrophic cardiomyopathy 4	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Intron variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID:18337725). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000138326). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002498624	SCV002807914	likely pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-11-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149866	SCV003837595	likely pathogenic	Cardiomyopathy	2023-06-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000788553	SCV003916712	likely pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000467263	SCV004175663	pathogenic	Hypertrophic cardiomyopathy	2023-04-12	criteria provided, single submitter	clinical testing	The MYBPC3 c.1224-19G>A variant is classified as Likely Pathogenic (PVS1_Moderate, PS4_Moderate, PM2) MYBPC3 c.1224-19G>A is located in intron 13/34. The variant has been reported in at least 10 proband with a clinical presentation of Hypertrophic Cardiomyopathy (PMID#18258667, 18337725, 33673806, 31006259, 34400558) (PS4_Moderate) and is rare in population databases (gnomAD allele frequency = 0.0025%; 5 het) (PM2). The variant has been reported in dbSNP (rs587776699), in the HGMD database as disease causing (CS081936) and is reported as Likely pathogenic by other diagnostic laboratories (ClinVar#138326). RT-PCR studies confirm this variant results in a 17nt extension of exon 14 which results in a premature termination codon in exon 15 of MYBPC3 (PMID#18337725). This paper suggests the variant may result in a weak denovo splice site and it is unclear what fraction of pre-mRNA is incorrectly spliced (PVS1_Moderate).
OMIM	RCV000009149	SCV000029366	pathogenic	Hypertrophic cardiomyopathy 4	2008-09-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000788553	SCV001922987	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000788553	SCV001928124	uncertain significance	not provided		no assertion criteria provided	clinical testing