ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.927-9G>A (rs397516083)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000473914 SCV000059334 pathogenic Hypertrophic cardiomyopathy 2020-11-17 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 as Pathogenic by multiple clinical laboratories in ClinVar (Variation ID 42807) and has been identified in 1/95618 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.
GeneDx RCV000158321 SCV000208256 pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing The c.927-9 G>A variant in the MYBPC3 gene has previously been reported in association with HCM and co-segregation with disease has been observed in multiple families (Rodriguez-Garcia et al., 2010; Ho et al., 2013; Caselli et al., 2014; Das et al., 2014). In addition, this variant has been observed in several other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and another laboratory reported co-segregation of this variant with disease in 4 affected family members (ClinVar SCV000059334.4; Landrum et al., 2016). The c.927-9 G>A variant is observed in 1/30900 (0.003%) alleles in large population cohorts (Lek et al., 2016). In silico splice prediction programs predict that the c.927-9 G>A variant creates a new splice acceptor site upstream of the natural splice acceptor site for intron 11. Functional studies demonstrated that the c.927-9 G>A variant leads to skipping of exon 12 and results in haploinsufficiency due to the creation of an unstable transcript (Helms et al., 2014; Crehalet et al., 2012). We interpret c.927-9 G>A as a pathogenic variant.
Blueprint Genetics RCV000208378 SCV000264050 pathogenic Primary familial hypertrophic cardiomyopathy 2015-12-07 criteria provided, single submitter clinical testing
Invitae RCV000473914 SCV000546426 pathogenic Hypertrophic cardiomyopathy 2020-10-28 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, but it affects a nucleotide within the consensus splice site of the intron. 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 (ExAC no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28615295, 24113344, 23549607, 29121657, 26914223, 29030401, 24810389). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42807). Studies have shown that this variant is associated with inclusion of intron 11, which introduces a frameshift (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 Familial 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 Familial 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 2017-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170203 SCV001358526 pathogenic Cardiomyopathy 2021-02-22 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). This splice acceptor site was not recognized by most computational splice prediction algorithms, suggesting that it may be a weak splice site. 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 cause a 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). 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 Familial 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
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

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