Submissions for variant NM_000256.3(MYBPC3):c.3330+5G>C

dbSNP: rs373746463

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000197890	SCV000059231	pathogenic	Hypertrophic cardiomyopathy	2019-04-04	criteria provided, single submitter	clinical testing	The c.3330+5G>C variant in MYBPC3 has been reported in >12 individuals with HCM and segregated with disease in 8 affected relatives from 3 families (Watkins 1995, Captur 2014, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID 7493025) and has been identified in 7/22230 African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org). This variant has been shown to cause skipping of exon 30, resulting in a frameshift and premature stop codon, which is predicted to lead to truncated or absent protein (Watkins 1995). Heterozygous loss of MYBPC3 function is an established disease mechanism in individuals with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon presence in multiple affected individuals, very low frequency in the general population, segregation studies and the predicted impact to the protein. ACMG/AMP Criteria applied (Richards 2015): PS4_moderate, PM2, PP1_Strong, PVS1.
GeneDx	RCV000223725	SCV000208166	pathogenic	not provided	2022-04-04	criteria provided, single submitter	clinical testing	Splice site variant demonstrated to result in loss-of-function (Watkins et al., 1995); Other splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with cardiomyopathy, including two other nucleotide substitutions at the same intronic position (c.3330+5 G>T, c.3330+5 G>A) (HGMD); This variant is associated with the following publications: (PMID: 24033266, 23782526, 25351510, 29121657, 30550750, 7493025, 23534983, 24704860, 28518168, 26688388, 28679633, 28138913, 29212898, 25611685, 23054336, 31028938, 31447099, 33906374)
Invitae	RCV000197890	SCV000253814	pathogenic	Hypertrophic cardiomyopathy	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 30 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 (rs373746463, gnomAD 0.03%). This variant has been observed in individual(s) with familial hypertrophic cardiomyopathy (PMID: 7493025). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42706). 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 30 and introduces a premature termination codon (PMID: 7493025). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000247970	SCV000320055	pathogenic	Cardiovascular phenotype	2023-12-27	criteria provided, single submitter	clinical testing	The c.3330+5G>C intronic alteration consists of a G to C substitution 5 nucleotides after coding exon 30 in the MYBPC3 gene. Based on data from gnomAD, the C allele has an overall frequency of 0.003% (7/258400) total alleles studied. The highest observed frequency was 0.031% (7/22340) of African alleles. This variant was reported to cause skipping of exon 30 in lymphocytes from affected individuals and segregated with hypertrophic cardiomyopathy (HCM) in six individuals from three generations in one family (Watkins, 1995). This variant has also been detected in additional unrelated individuals with HCM (Miller, 2013; Alfares, 2015) This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515249	SCV000611210	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-17	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001027858	SCV001190489	likely pathogenic	Hypertrophic cardiomyopathy 4	2020-01-06	criteria provided, single submitter	research	ACMG codes: PS3, PP1, PP3, PP5
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171129	SCV001333810	pathogenic	Cardiomyopathy	2023-05-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193928	SCV001363103	pathogenic	Primary familial hypertrophic cardiomyopathy	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.3330+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site and two predict it weakens a 5' donor site. At least two publications report experimental evidence that this variant affects mRNA splicing (Watkins_1995, Ito_2017). The variant allele was found at a frequency of 1.8e-05 in 227264 control chromosomes (gnomAD and publication). c.3330+5G>C has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Watkins_1995, Nunez_2013, Captur_2014, Miller_2017), including a large family in which the variant segregated with the disease (Watkins_1995). These data indicate that the variant is very likely to be associated with disease. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001027858	SCV001423819	pathogenic	Hypertrophic cardiomyopathy 4	2020-01-14	criteria provided, single submitter	research
AiLife Diagnostics, AiLife Diagnostics	RCV000223725	SCV002501668	pathogenic	not provided	2021-12-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147317	SCV003836008	pathogenic	Left ventricular noncompaction 10	2022-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001027858	SCV003836019	pathogenic	Hypertrophic cardiomyopathy 4	2022-11-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001027858	SCV004101279	pathogenic	Hypertrophic cardiomyopathy 4	2023-07-25	criteria provided, single submitter	clinical testing	The MYBPC3 c.3330+5G>C variant, also known as IVS30+5G>C, results in the substitution of a guanine with a cytosine within a splice region near a canonical splice donor site. Functional studies have shown that this variant results in the skipping of exon 30, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein (PMID: 7493025; PMID: 28679633). Loss of normal protein function through nonsense-mediated mRNA decay is expected. This variant has been identified in individuals with hypertrophic cardiomyopathy (PMID: 7493025; PMID: 23534983; PMID: 24704860; PMID: 29212898; PMID: 30550750). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been shown to segregate with disease in a multigenerational family (PMID: 7493025). Based on the available evidence, the MYBPC3 c.3330+5G>C variant is classified as pathogenic for hypertrophic cardiomyopathy.
Mayo Clinic Laboratories, Mayo Clinic	RCV000223725	SCV004226846	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	PP1_moderate, PS3, PS4_moderate, PVS1
All of Us Research Program, National Institutes of Health	RCV000197890	SCV004830298	pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +5 position of intron 30 of the MYBPC3 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have confirmed that this variant causes aberrant splicing, resulting in out-of-frame skipping of exon 30 and premature truncation (PMID: 7493025, 28679633). This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 7493025, 23782526, 24704860, 25611685, 28193612, 29121657, 29212898, 30550750, 35508642, 36704059). It has been shown that this variant segregates with disease in affected families (PMID: 7493025, 24704860, ClinVar SCV000059231.5). This variant has been identified in 7/258400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clincalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223725	SCV000280261	likely pathogenic	not provided	2015-06-18	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 IVS30+5 G>C Based on the data reviewed below we consider this variant likely disease-causing. The variant has been reported previously in one family with HCM (Watkins H et al., 1995). Many protein-truncating variants have been reported in MYBPC3 in association with HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003), and splice variants in MYBPC3 are a well-established cause of HCM. . The variant was showed to lead to an aberrant splice transcript due to skipping of exon 30, shift in the reading frame, and premature termination of translation in exon 31. In total the variant has not been seen in ~6,600 published controls and individuals from publicly available population datasets. There is no variation at c.3330+5 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,5000 Caucasian and African American individuals (as of 9/20/13). There are only two individuals reported in this cohort with splice donor variants in MYBPC3. The variant was not observed in the following published control samples: Watkins et al, not present in 100 control individuals.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000223725	SCV001807074	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000223725	SCV001918982	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000223725	SCV001932099	pathogenic	not provided		no assertion criteria provided	clinical testing