Submissions for variant NM_000256.3(MYBPC3):c.1224-52G>A

gnomAD frequency: 0.00002  dbSNP: rs786204336

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV004786484	SCV001245082	likely pathogenic	Hypertrophic cardiomyopathy 4	2018-07-11	criteria provided, single submitter	research	MYBPC3 c.1224-52G>A has been identified previously by another laboratory in a control sample (Genetics Diagnostic Laboratory, CHEO, ClinVar:SCV000219698.2). We identified this variant in two HCM probands, and for one family it was found to segregate to one first-degree family member (Bagnall et al., 2018). This variant is present at a low frequency in the Genome Aggregation Database (MAF=0.00003; http://gnomad.broadinstitute.org/), and is absent in Bravo (http://bravo.sph.umich.edu). Splice prediction tools SpliceSiteFinder, MaxEntScan and NNsplice all predict the variant disrupts splicing. RNA studies showed that this variant results in the creation of a new acceptor site which causes an additional 50 base pairs to be spliced in with exon 14, this would cause a shift in the reading frame downstream and consequently a premature stop codon (Bagnall RD et al., 2018). Based on the adapted ACMG guidelines (Kelly et al., 2018), RNA studies show this variant results altered splicing (PS3), the variant is rare in the general population (PM2), and has been identified in at least 2 HCM probands, therefore we classify MYBPC3 c.12224-52G>A as 'likely pathogenic'.
Color Diagnostics, LLC DBA Color Health	RCV001176081	SCV001339919	pathogenic	Cardiomyopathy	2024-07-23	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -52 position of intron 13 of the MYBPC3 gene. RNA studies have shown that this variant causes inclusion of 50 intronic nucleotides, resulting in a frameshift and premature translation stop signal (PMID: 30025578, 32163302, 33657327). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyoathy (PMID: 30025578, 32163302, 32396390, 33657327, 35288587, 35508642), and in an individual affected with sudden death (PMID: 38489124). In a study of a large cohort of individuals affected with hypertrophic cardiomyopathy, this variant was observed in 55 individuals out of a total of 5393 affected individuals (PMID: 32163302). It has been shown that this variant segregates with disease in multiple individuals across at least 9 families (PMID: 30025578, 32163302, 32396390, 35288587). This variant has been identified in 1/31334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001176081	SCV001519448	pathogenic	Cardiomyopathy	2021-03-12	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.1224-52G>A is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3' acceptor site. Experimental evidence has shown that this variant affects mRNA splicing, causing inclusion of 50 intronic nucleotides, leading to a frameshift in the amino acid sequence and insertion of premature termination codon (p.Ser408fs*31; Bagnall_2018, Harper_2020). The variant was absent in 173584 control chromosomes (gnomad). c.1224-52G>A has been reported in the literature in multiple individuals affected with HCM, has been shown to segregate with disease in several families and has been reported as a recurrent and frequenct mutation in HCM patients (Harper_2020, Lopes_2020). Due to the deep intronic location of this variant, it has rarely been covered by studies in the literature, and thus has only recently been reported as a novel variant. Based on the case-control data reported by Harper et al., this variant has a large effect size (odds ratio of 780, p-value 9.7x10-64), suggesting it is a high penetrance allele. In addition, the variant has been found to be in strong linkage disequilirium (although not complete linkage disequilibrium) with the well-reported risk variant c.3628-41_3628-17del, and recent genetic analysis suggests that this risk variant may not directly confer an increased risk of cariomyopathy but instead act as a marker for c.1224-52G>A (Harper_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, c.1224-52G>A was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001089608	SCV001579888	pathogenic	Hypertrophic cardiomyopathy	2025-01-29	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 altered protein product. This variant is present in population databases (rs786204336, gnomAD 0.01%). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 30025578, 32163302, 32396390). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188544). Studies have shown that this variant results in aberrant splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 30025578, 32163302). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001089608	SCV001652955	pathogenic	Hypertrophic cardiomyopathy	2023-10-18	criteria provided, single submitter	clinical testing	The c.1224-52G>A variant in MYBPC3 has been reported in > 30 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 7 affected relatives from 5 families (Bagnall 2018 PMID: 30025578, Harper 2020 PMID: 32163302). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 188544) and has also been identified in 0.003% (2/68000) of European chromosomes and 0.002% (1/41364) of African chromosomes but is absent from all other populations in gnomAD, including the South Asian population (http://gnomad.broadinstitute.org, v.3.1.2). Computational splice prediction tools predict an impact on splicing through the creation of a new donor splice site which was also corroborated by functional studies using patient RNA from blood. These showed that this variant impacted splicing, resulting in the inclusion of 50 additional intronic nucleotides that results in a frameshift that leads to a premature termination codon 30 amino acids downstream (Bagnall 2018 PMID: 30025578, Harper 2020 PMID: 32163302). This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Moderate, PP3.
GeneDx	RCV001778767	SCV002015571	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Non-canonical splice site variant demonstrated to result in loss-of-function (Bagnall et al., 2018); Reported in ClinVar (ClinVar Variant ID# 188544 ; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30025578, 32163302, 32543992, 32396390, 33657327, 33673806, 33724884)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001176081	SCV002042121	pathogenic	Cardiomyopathy	2023-06-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288775	SCV002581192	pathogenic	Left ventricular noncompaction 10	2021-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354412	SCV002656058	pathogenic	Cardiovascular phenotype	2023-04-13	criteria provided, single submitter	clinical testing	The c.1224-52G>A intronic pathogenic mutation results from a G to A substitution 52 nucleotides upstream from coding exon 14 in the MYBPC3 gene. This mutation has been reported in individuals with hypertrophic cardiomyopathy (HCM) and has been shown to segregate with disease in affected family members from multiple families (Bagnall RD et al. J. Am. Coll. Cardiol., 2018 07;72:419-429; Harper AR et al. Circ Genom Precis Med, 2020 06;13:e002783). RNA analysis from affected individuals confirmed the insertion of 50 additional nucleotides (Bagnall RD et al. J. Am. Coll. Cardiol., 2018 07;72:419-429; Harper AR et al. Circ Genom Precis Med, 2020 06;13:e002783). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Genetics, Royal Melbourne Hospital	RCV001089608	SCV004812352	pathogenic	Hypertrophic cardiomyopathy	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change in MYBPC3 is an intronic variant located in intron 13. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.015% (12/78,060 alleles) in the South Asian population. The variant has been identified in ~1% of individuals with hypertrophic cardiomyopathy (HCM), a prevalence that is significantly increased compared with the prevalence in the population (PMID: 32396390). The variant has been reported to segregate with HCM in multiple unrelated families (PMID: 32163302, 32396390). This variant has been observed as homozygous in two siblings with severe infantile cardiomyopathy (PMID: 36980931). The results from an in silico splicing predictor (SpliceAI) indicate that this variant may impact splicing by disrupting the acceptor splice site of intron 13 of MYBPC3. This prediction is confirmed by RT-PCR and RNA sequencing. The assays demonstrated that the variant impacts splicing by apparently near complete cryptic acceptor activation leading to 50 bp intron 13 inclusion and an out-of-frame extension of exon 14 (p.Ser408fs*31; PMID: 30025578, 32163302, 33657327). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PP1_Strong, PS4.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786484	SCV005400587	pathogenic	Hypertrophic cardiomyopathy 4	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0217 - Non-coding variant with known effect. This variant has been shown to result in a 50bp retention of intron 13, leading to a frameshift and premature stop codon at residue 438 (PMIDs: 30025578, 32163302). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least twenty individuals with hypertrophic cardiomyopathy (VCGS, PMIDs: 30025578, 32163302). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate with disease in four unrelated families however, this variant has also been identified in one unaffected individual (PMID: 32163302). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001176081	SCV005420902	pathogenic	Cardiomyopathy	2024-10-04	criteria provided, single submitter	research	PVS1,PP1,PS4,PM2
All of Us Research Program, National Institutes of Health	RCV001089608	SCV005430036	pathogenic	Hypertrophic cardiomyopathy	2024-09-26	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -52 position of intron 13 of the MYBPC3 gene. RNA studies have shown that this variant causes inclusion of 50 intronic nucleotides, resulting in a frameshift and premature translation stop signal (PMID: 30025578, 32163302, 33657327). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyoathy (PMID: 30025578, 32163302, 32396390, 33657327, 35288587, 35508642), and in an individual affected with sudden death (PMID: 38489124). In a study of a large cohort of individuals affected with hypertrophic cardiomyopathy, this variant was observed in 55 individuals out of a total of 5393 affected individuals (PMID: 32163302). It has been shown that this variant segregates with disease in multiple individuals across at least 9 families (PMID: 30025578, 32163302, 32396390, 35288587). This variant has been identified in 1/31334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005049448	SCV005684638	likely pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2024-04-21	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004552940	SCV005900667	pathogenic	MYBPC3-related disorder	2023-11-02	criteria provided, single submitter	clinical testing	This intronic variant is located 52 nucleotides upstream of the intron 13/exon 14 boundary. This is a known Pathogenic variant that has been previously reported as a heterozygous or homozygous change in individuals with hypertrophic cardiomyopathy (PMID: 30025578, 32163302, 32396390, 33657327, 36980931). Functional study findings demonstrated that the c.1224-52G>A variant resulted in aberrant splicing that introduces a premature termination codon, causing the mRNA to undergo nonsense mediated decay (PMID: 33657327). The c.1224-52G>A variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (1/31334) and thus is presumed to be rare. Based on the available evidence, c.1224-52G>A is classified as Pathogenic.
3billion	RCV004786484	SCV005906063	pathogenic	Hypertrophic cardiomyopathy 4	2023-08-02	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%). Predicted Consequence/Location: Intron variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.99 (>=0.2, moderate evidence for spliceogenicity)]. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 30025578, 32163302, 32396390). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 32396390). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000188544 /PMID: 30025578). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Illumina Laboratory Services, Illumina	RCV004786484	SCV006059897	likely pathogenic	Hypertrophic cardiomyopathy 4	2024-03-01	criteria provided, single submitter	clinical testing	The MYBPC3 c.1224-52G>A variant occurs in an intron and has been identified in at least 30 unrelated individuals with hypertrophic cardiomyopathy (PMID: 32396390; 35508642). Functional studies conducted in patient cells demonstrated that the c.1224-52G>A variant affects mRNA splicing, causing inclusion of 50 nucleotides, leading to a shift in the protein reading frame that is predicted to result in premature termination of the protein (PMID: 30025578; 32163302; 33657327). The c.1224-52G>A variant is not observed at a significant frequency in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. This variant has been shown to segregate with disease across multiple families (PMID: 32163302). Based on the available evidence, the c.1224-52G>A variant is classified as likely pathogenic for hypertrophic cardiomyopathy.
PreventionGenetics, part of Exact Sciences	RCV004552940	SCV004111936	pathogenic	MYBPC3-related disorder	2024-06-27	no assertion criteria provided	clinical testing	The MYBPC3 c.1224-52G>A variant is predicted to interfere with splicing. This variant has been reported in numerous individuals with hypertrophic cardiomyopathy (Bagnall et al. 2018. PubMed ID: 30025578; Harper et al. 2020. PubMed ID: 32163302; Lopes et al. 2020. PubMed ID: 32396390; Table S1, Lesurf et al. 2022. PubMed ID: 35288587). mRNA studies showed that this variant results in the inclusion of 50 intronic nucleotides leading to a frameshift and premature protein termination p.Ser408fs*31 (Bagnall et al. 2018. PubMed ID: 30025578; Harper et al. 2020. PubMed ID: 32163302; Holliday et al. 2021. PubMed ID: 33657327). This variant is reported in 0.012% (1/8,688) of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.