Variant classification summary

NM_000256.3:c.1504C>T

MYBPC3 · NP_000247.2:p.(Arg502Trp) · NM_000256.3

GRCh37: chr11:47364249 G>A · GRCh38: chr11:47342698 G>A

Gene: MYBPC3 Transcript: NM_000256.3

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting PP1 supporting

Variant details

Gene

MYBPC3

Transcript

NM_000256.3

Protein

NP_000247.2:p.(Arg502Trp)

gnomAD AF

0.000144371136677952 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Supporting PS3: Arg502Trp-associated HCM tissue showed approximately 24% lower MyBP-C content than donor tissue.

2

Moderate PM1: codon 502 lies within the VCEP-approved MYBPC3 missense cluster region.

3

Supporting PM2: gnomAD v2.1.1 non-founder populations meet the no-more-than-one-allele criterion.

4

Supporting PP1: familial cosegregation yielded a combined LOD score of 4.04.

Final determination: Under the MYBPC3 VCEP criteria-combination framework, PS3 supporting, PM1 moderate, PM2 supporting, and PP1 supporting do not meet any pathogenic or benign rule, so the final call is VUS.

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	N/A	Not applicable: c.1504C>T is a missense SNV producing p.Arg502Trp, not one of the VCEP-specified null variant classes required for PVS1.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: no distinct qualifying variant producing the same p.Arg502Trp amino-acid change was documented.	cspec PMID:20378854 PMID:12707239
PS2	Not assessed	Not assessed: confirmed maternity, paternity, and unaffected-parent cardiac evaluation are not documented for this variant.	cspec
PS3	Met	Met at Supporting: human myectomy tissue showed approximately 24% lower MyBP-C content in MYBPC3-mutant samples, including Arg502Trp, versus donor tissue.	cspec PMID:19574547
PS4	Not met	Not met: 34/1,414 HCM cases versus 0/545 controls gives continuity-corrected OR 27.27, but the 95% CI lower bound is 1.67, below the VCEP threshold of >=5.	cspec PMID:20378854 PMID:12707239 PMID:16199542 PMID:18409188 PMID:19574547 PMID:21267010
PM1	Met	Met at moderate: p.Arg502Trp is a missense variant at codon 502, within the VCEP-approved MYBPC3 region 485-502.	cspec PMID:20378854 PMID:12707239
PM2	Met	Met at supporting: gnomAD v2.1 non-cancer exomes show one Other allele (1/6,626) and zero Ashkenazi Jewish alleles, satisfying the VCEP ≤1-allele alternative.	cspec gnomad_v2
PM3	N/A	Not applicable: the MYBPC3 VCEP explicitly marks PM3 as Not Applicable.	cspec
PM4	N/A	Not applicable: the variant is a missense SNV with no in-frame deletion, insertion, stop-loss event, or protein-length change under the VCEP PM4 rule.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no qualifying different missense variant at MYBPC3 codon 502 was documented for amino-acid impact comparison.	cspec PMID:12707239
PM6	Not assessed	Not assessed: no assumed de novo occurrence without confirmed maternity and paternity is documented for this variant.	cspec
PP1	Met	Met at supporting: familial cosegregation produced a combined LOD score of 4.04, exceeding the VCEP supporting threshold of LOD 0.9.	cspec PMID:20378854
PP2	N/A	Not applicable: the MYBPC3 VCEP explicitly marks PP2 as not applicable.	cspec
PP3	Not met	Not met: REVEL 0.64 is below the VCEP PP3 threshold of >=0.70, while SpliceAI's maximum delta score is only 0.004.	cspec revel spliceai
PP4	N/A	Not applicable: the VCEP excludes PP4 because inherited cardiomyopathies have high locus heterogeneity and non-genetic etiologies.	cspec
PP5	N/A	Not applicable: the VCEP states that PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	Not met: gnomAD v4.1 popmax FAF is 0.000166, below the VCEP BA1 threshold of ≥0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 popmax FAF is 0.000166, below the VCEP MYBPC3 BS1 threshold of ≥0.0002.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the MYBPC3 VCEP explicitly designates BS2 as Not Applicable.	cspec
BS3	Not assessed	Not assessed: the available Arg502Trp tissue study showed reduced MyBP-C abundance, not a benign or normal functional result.	cspec PMID:19574547
BS4	Not assessed	Not assessed: no affected variant-negative relatives are documented, and the VCEP requires at least 2 credible non-segregations.	cspec PMID:20378854
BP1	N/A	Not applicable: the MYBPC3 VCEP explicitly marks BP1 as not applicable.	cspec
BP2	Not assessed	Not assessed: qualifying phase and at least 2 cases are unestablished, while additional-mutation carriers reportedly had more severe disease.	cspec PMID:20378854
BP3	N/A	Not applicable: the MYBPC3 VCEP explicitly designates BP3 as not applicable to the current genes.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.64 exceeds the VCEP BP4 threshold of <=0.40, despite SpliceAI showing a maximum delta score of 0.004.	cspec revel spliceai
BP5	N/A	Not applicable: the VCEP excludes BP5 and states that a non-cardiomyopathy pathogenic variant does not reduce independent cardiomyopathy causality.	cspec
BP6	N/A	Not applicable: the VCEP states that BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	Not applicable: BP7 is limited to synonymous or specified intronic variants, whereas this variant is the exon 17 missense change p.Arg502Trp.	cspec

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