Submissions for variant NM_000256.3(MYBPC3):c.927-9G>A

gnomAD frequency: 0.00002  dbSNP: rs397516083

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000473914	SCV000059334	pathogenic	Hypertrophic cardiomyopathy	2021-09-23	criteria provided, single submitter	clinical testing	The c.927-9G>A variant in MYBPC3 has been reported in >20 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 8 affected individuals from 7 families (Rodriguez-Garcia 2010 PMID: 21488307, Rodriguez-Garcia 2010 PMID: 20433692, Crehalet 2012, Das 2014 PMID: 24113344, Murphy 2016 PMID: 26914223, Viswanathan 2017 PMID: 29121657, Marschall 2019 PMID: 31737537, O'Leary 2019 PMID: 30550750, LMM data). It has also been reported by multiple clinical laboratories in ClinVar (Variation ID 42807) and has been identified in 0.001% (1/95618) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the conserved splice consensus sequence and in vitro splicing studies suggest that it disrupts splicing, leading to an abnormal or absent protein (Crehalet 2012, Helms 2014 PMID: 25031304). In summary, the c.927-9G>A variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2_Supporting.
GeneDx	RCV000158321	SCV000208256	pathogenic	not provided	2022-02-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that c.927-9 G>A leads to skipping of exon 12 and results in either an abnormal truncated protein or haploinsufficiency due to the creation of an unstable transcript (Helms et al., 2014; Crehalet et al., 2012); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 42807); This variant is associated with the following publications: (PMID: 21488308, 31737537, 25217454, 27834932, 21415409, 31028938, 25031304, 24113344, 23549607, 24810389, 20433692, 27688314, 26914223, 28916354, 28790153, 29121657, 30645170, 31006259, 33673806, 31589614, 30550750, 32746448, 28679633, 31447099, 34135346)
Blueprint Genetics	RCV000208378	SCV000264050	pathogenic	Primary familial hypertrophic cardiomyopathy	2015-12-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473914	SCV000546426	pathogenic	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 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. 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 variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23549607, 24113344, 24810389, 26914223, 28615295, 29030401, 29121657). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS11-9G>A. ClinVar contains an entry for this variant (Variation ID: 42807). 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 inclusion of intron 11 and introduces a premature termination codon (PMID: 25031304). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515159	SCV000611212	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2017-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208378	SCV000696335	pathogenic	Primary familial hypertrophic cardiomyopathy	2021-05-03	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.927-9G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing, however at least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in skipping of exon 12 (e.g. Crehalet_2012). The variant allele was found at a frequency of 5.4e-06 in 186306 control chromosomes. c.927-9G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Rodriguez-Garcia_2010, Crehalet_2012, Das_2014), and co-segregated with disease in multiple families (Rodriguez-Garcia_2010, Das_2014). These data indicate that the variant is very likely to be associated with disease. 11 other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709744	SCV000840018	pathogenic	Hypertrophic cardiomyopathy 4	2017-08-21	criteria provided, single submitter	clinical testing	A heterozygous c.927-9G>A pathogenic variant in the MYBPC3 gene was detected in this individual. This variant has been previously as disease-causing (PMID: 21488308, 24113344, 23549607; 26914223). Studies characterizing the effect of the c.927-9G>A variant on MYBPC3 function have shown splicing at exon 11 is absent and protein levels are reduced (PMID: 25031304). Therefore, this variant is classified as a pathogenic variant in accordance with ACMG guidelines.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170203	SCV001332755	pathogenic	Cardiomyopathy	2023-06-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170203	SCV001358526	pathogenic	Cardiomyopathy	2023-01-25	criteria provided, single submitter	clinical testing	This variant is located in intron 11 of the MYBPC3 gene (also known as IVS11-9G>A in literature). A mini-gene splicing assay has shown that the wild type construct results in approximately equal amounts of the normal transcript and the short transcript lacking exon 12, suggesting that the weak acceptor site of intron 11 was not always recognized (Crehalet 2012, doi.org/10.4081/cardiogenetics.2012.e6). This study has also shown that this variant causes complete skipping of exon 12, which is expected to result in frameshift and premature translation stop. In a study using ventricular myocardial tissue from an individual affected with hypertrophic cardiomyopathy, this variant has been shown to cause inclusion of intron 11 and premature truncation in ~40% of the transcripts (PMID: 25031304). A recent study using RNA samples from two affected carriers did not detect aberrant splicing, although the possibility of RNA degradation cannot be ruled out (PMID: 30645170). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 23549607, 24113344, 26914223, 28408708, 28615295, 28790153, 29030401, 33658374, 35508642). This variant has also been reported to segregate with hypertrophic cardiomyopathy in multiple families (PMID: 20433692, 24113344; communication with external laboratory, ClinVar SCV000059334.6). This variant has been identified in 2/217270 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000709744	SCV001440502	pathogenic	Hypertrophic cardiomyopathy 4	2019-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000158321	SCV001448085	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000709744	SCV002059661	pathogenic	Hypertrophic cardiomyopathy 4	2020-12-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000158321	SCV004184148	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MYBPC3: PP1:Strong, PM2, PS3:Moderate, PS4:Moderate
All of Us Research Program, National Institutes of Health	RCV000473914	SCV004814327	pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This variant is located in intron 11 of the MYBPC3 gene (also known as IVS11-9G>A in literature). A mini-gene splicing assay has shown that the wild type construct results in approximately equal amounts of the normal transcript and the short transcript lacking exon 12, suggesting that the weak acceptor site of intron 11 was not always recognized (Crehalet 2012, doi.org/10.4081/cardiogenetics.2012.e6). This study has also shown that this variant causes complete skipping of exon 12, which is expected to result in frameshift and premature translation stop. In a study using ventricular myocardial tissue from an individual affected with hypertrophic cardiomyopathy, this variant has been shown to cause inclusion of intron 11 and premature truncation in ~40% of the transcripts (PMID: 25031304). A recent study using RNA samples from two affected carriers did not detect aberrant splicing, although the possibility of RNA degradation cannot be ruled out (PMID: 30645170). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 23549607, 24113344, 26914223, 28408708, 28615295, 28790153, 29030401, 33658374, 35508642). This variant has also been reported to segregate with hypertrophic cardiomyopathy in multiple families (PMID: 20433692, 24113344; communication with external laboratory, ClinVar SCV000059334.6). This variant has been identified in 2/217270 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000158321	SCV005199344	pathogenic	not provided	2023-01-05	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158321	SCV000280287	likely pathogenic	not provided	2013-04-05	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 IVS11-9G>A This variant has been seen in at least 30 presumably unrelated cases of HCM (4 published, >26 unpublished). Four of >30 patients who had another variant: -One patient with p.Arg502Trp in MYBPC3 (pathogenic), with a severe phenotype and segregation consistent with two pathogenic variants. -One patient with p.Arg278Cys (c.832C>T) in TNNT2 (ClinVar: VUS by LMM, Blueprint, CHEO, Semsarian’s group; pathogenic by GeneDx), with severe phenotype, no segregation data. -One patient with p.Asn47Lys (c.141C>A) in MYL2 (ClinVar: VUS by LMM, Blueprint; pathogenic by GeneDx), diagnosed 56yo with LVWT 24 mm. -One patient with c.2864del in MYBPC3 (not in ClinVar, not published, ERA classifies as pathogenic), diagnosed 54yo with LVWT 21 mm. There is moderate segregation data. In 5 families an additional affected relative carried this variant. In total, the variant has not been seen in at least 6326 and as many as 64,326 individuals from presumably unrelated published and database controls. Both in silico and in vitro data suggest that this variant causes aberrant splicing (Crehalet, 2012). Published cases: Rodriguez-Garcia (2010) reported this variant in 2 patients diagnosed with HCM cared for in Complejo Hospitalario Universitario A Coruña, Spain, who underwent analysis of 537 genetic variants of HCM disease genes - TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC, TTN, MYH6, MYLK2, MYO6, and TCAP. No phenotype information is provided for the two patients. Authors report 1 affected male has an affected daughter with this variant. Crehalet (2012) reported this variant in 2 patients diagnosed with HCM cared for in Bron, Lyon, and Nantes (France) who underwent sequencing analysis of MYBPC3, MYH7, TNNT2, and TNNI3 genes. One of the patients was 12-year old boy with HCM and the other was a 30-year old man with HCM and atrial fibrillation. Gruner (2014) reported this variant in one “G+/P-“ patient cared for at the Tufts Medical Center or the Toronto General Hospital. The patient is a 27-year-old woman with a normal maximum left ventricular thickness of 11 mm and no LVOT obstruction was present. Her family history was not reported. This variant is located in flanking intronic regions of intron 11. According to Crehalet et al (2012), the weak acceptor splice site of intron 11 was detected by Human Splicing Finder (HSF) which predicted the creation of a new acceptor site at position c.927-9, which is stronger than the wild type. In addition, HeLa cells transfected with the wild type sequence showed two different transcripts: a 410 bp normal product containing exon 12 and the 248 bp product corresponding to exon 12 skipping, as for the wild type minigene c.1090G, confirming that the weak acceptor site of intron 11 is not always recognized in HeLa cells. Furthermore, mutant minigene assay showed complete exon 12 skipping and the transcript lacking exon 12 would encode a truncated protein. Additional MYBPC3 splice variants reported in association with HCM include: IVS2-1G>A, IVS6-2A>C IVS7+1G>A, IVS8+1G>A, IVS12-2A>G, IVS14-2A>G, IVS16-1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A. The base is conserved across mammals with the exception of Cape golden mole (T). In total the variant has not been seen in at least 6326 and as many as 64,326 individuals from published controls and publicly available datasets that approximate the general population. The variant is absent in European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), which includes data on ~6,000 individuals of European or African American backgrounds. It is also not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of April 22nd, 2015). We think that this dataset goes sufficiently far into introns to provide data on this variant, but we are awaiting confirmation of that from the ExAC group. This variant is currently listed in dbSNP: rs397516083. The variant was not observed in the following published control samples: Gruner, 2014 in 126 control individuals and Rodriguez-Garcia, 2010 in 200 control individuals.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000473914	SCV000804885	pathogenic	Hypertrophic cardiomyopathy	2016-05-19	no assertion criteria provided	clinical testing