Variant classification summary

NM_000256.3:c.2373dup

MYBPC3 · NP_000247.2:p.(Trp792ValfsTer41) · NM_000256.3

GRCh37: chr11:47359280 A>AC · GRCh38: chr11:47337729 A>AC

Gene: MYBPC3 Transcript: NM_000256.3

Final call

Pathogenic

PVS1 very strong PS3 supporting PM2 supporting PP3 supporting

Variant details

Gene

MYBPC3

Transcript

NM_000256.3

Protein

NP_000247.2:p.(Trp792ValfsTer41)

gnomAD AF

2.6856967464702272e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 is very strong because the exon 24 frameshift truncates MYBPC3 at p.792, before the p.1254 NMD-escape boundary.

2

Pathogenic: PS3 is supporting because cardiac studies showed abnormal transcript processing, absent truncated protein, reduced cMyBP-C, and impaired cardiomyocyte force.

3

Pathogenic: PM2 is supporting because the variant meets the MYBPC3 VCEP's gnomAD v2.1.1 non-founder-population rarity path.

4

Pathogenic: PP3 is supporting because SpliceAI predicts a possible splice impact with a maximum delta score of 0.351.

Final determination: Under VCEP Rule4, one very strong pathogenic criterion plus at least two supporting pathogenic criteria yields a Pathogenic classification.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met, very strong: the exon 24 frameshift truncates MYBPC3 at p.792, well before the VCEP's p.1254 NMD-escape boundary.	cspec pvs1_variant_assessment pvs1_gene_context PMID:19273718
PS1	N/A	Not applicable: c.2373dup produces p.Trp792ValfsTer41, a frameshift with no missense amino-acid substitution for PS1 comparison.	cspec
PS2	Not assessed	Not assessed: no confirmed de novo proband with documented parental genotypes and cardiac evaluations is available.	cspec PMID:10736283
PS3	Met	Met at Supporting: cardiac studies of seven c.2373dupG carriers showed absent truncated protein, 33% lower full-length cMyBP-C, and reduced cardiomyocyte force.	cspec PMID:19273718
PS4	Not assessed	Not assessed: affected-carrier reports lack an eligible control denominator, so the VCEP-required OR and 95% CI cannot be calculated against the >=5 supporting threshold.	cspec PMID:14563344 PMID:10736283
PM1	N/A	Not applicable: PM1 is limited to missense variants, whereas c.2373dup is a frameshift producing p.Trp792ValfsTer41.	cspec
PM2	Met	Met at Supporting: gnomAD v2.1 non-cancer exomes show 0 alleles in both Other and Ashkenazi Jewish non-founder populations, satisfying the VCEP PM2 path.	cspec gnomad_v2
PM3	N/A	Not applicable: the MYBPC3 VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: c.2373dup is a frameshift, whereas the VCEP defines PM4 for in-frame insertions/deletions or stop-loss variants.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires a different missense variant at the same codon, but c.2373dup is a frameshift.	cspec
PM6	Not assessed	Not assessed: no assumed de novo proband with sufficient phenotype characterization and parental information is documented.	cspec PMID:10736283
PP1	Not assessed	Not assessed: cosegregation is reported, but the number of qualifying genotype-positive/phenotype-positive segregations is not provided to compare with the ≥3 threshold.	cspec PMID:10736283
PP2	N/A	Not applicable: the MYBPC3 VCEP explicitly marks PP2 as Not Applicable.	cspec
PP3	Met	Met at Supporting: SpliceAI predicts a possible splice impact with maximum delta score 0.351, including DS_DG=0.351.	cspec spliceai
PP4	N/A	Not applicable: the MYBPC3 VCEP explicitly marks PP4 as Not Applicable.	cspec
PP5	N/A	Not applicable: the MYBPC3 VCEP explicitly marks PP5 as Not Applicable despite a reported pathogenic classification in an affected-neonate case series.	cspec
BA1	Not met	Not met: gnomAD v4.1 popmax FAF is 2.642e-05, below the VCEP BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 popmax FAF is 2.642e-05, below the VCEP BS1 threshold of 0.0002.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the MYBPC3 VCEP explicitly marks BS2 as Not Applicable, regardless of the zero observed homozygotes.	cspec
BS3	Not assessed	Not assessed: the available cardiac assay showed reduced cMyBP-C and contractile force, not preserved function or absence of splicing impact.	cspec PMID:19273718
BS4	Not assessed	Not assessed: no qualifying non-segregations are documented, whereas the VCEP requires at least 2 unlikely phenocopy or alternate-variant events.	cspec PMID:10736283
BP1	N/A	Not applicable: the MYBPC3 VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no documented cis/trans relationship with another VCEP-defined pathogenic variant in at least two cases is available.	cspec PMID:19273718
BP3	N/A	Not applicable: the VCEP marks BP3 not applicable to MYBPC3, and this variant is a frameshift rather than an in-frame indel.	cspec pvs1_variant_assessment
BP4	N/A	Not applicable: this is a frameshift, so a splice prediction cannot establish no impact on the gene product for BP4.	cspec
BP5	N/A	Not applicable: the MYBPC3 VCEP explicitly marks BP5 as Not Applicable.	cspec
BP6	N/A	Not applicable: the MYBPC3 VCEP explicitly marks BP6 as Not Applicable.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or suitably distant intronic variants, whereas this variant is a coding frameshift in exon 24.	cspec

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