LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-31
Case ID: NM_000257.4_c.1208G_A_20261031_141528
Framework: ACMG/AMP 2015
Variant classification summary

NM_000257.4:c.1208G>A

MYH7  · NP_000248.2:p.(Arg403Gln)  · NM_000257.4
GRCh37: chr14:23898487 C>T  ·  GRCh38: chr14:23429278 C>T
Gene: MYH7 Transcript: NM_000257.4
Final call
Likely Pathogenic
PM1 moderate PM2 supporting PP1 strong PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MYH7
Transcript
NM_000257.4
Protein
NP_000248.2:p.(Arg403Gln)
gnomAD AF
6.194942448984649e-07 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM1 Moderate: p.Arg403Gln lies at codon 403 within the MYH7 VCEP HCM-enriched codon 167-931 region.
2
PM2 Supporting: gnomAD v4.1 European non-Finnish frequency is 1 allele in 1,180,040.
3
PP1 Strong: 20 affected genotype-positive Arg403Gln family members exceed the VCEP threshold of seven segregations.
4
PP3 Supporting: REVEL 0.886 exceeds the VCEP cutoff of 0.70.
Final determination: MYH7 VCEP Version 2.0 Rule11 is satisfied by one strong pathogenic criterion (PP1 Strong) and one moderate pathogenic criterion (PM1 Moderate), yielding Likely Pathogenic.
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: the MYH7 VCEP v2.0 entry explicitly marks PVS1 Not Applicable for this exon 13 missense variant.
cspec
PS1 Not met Not met: reviewed reports document p.Arg403Gln from c.1208G>A, but no different nucleotide change producing the same amino-acid change was identified.
cspec PMID:1975517 PMID:1638703 PMID:12975413
PS2 Not assessed Not assessed: one ClinVar record labels the variant de novo, but confirmed maternity, paternity, proband phenotype, and parental cardiac evaluations are not documented.
cspec clinvar
PS3 Not assessed Not assessed: functional-study leads lack auditable assay controls, reproducibility, and quantitative primary-source results required by the VCEP.
cspec
PS4 Not assessed Not assessed: affected-case reports exist, but no valid paired case-control denominators permit the VCEP-required OR and 95% CI threshold evaluation.
cspec vcep_cm_vcep_ps4_example_scenarios PMID:10725281 PMID:1638703 PMID:1975517
PM1 Met Met at Moderate: missense p.Arg403Gln is at codon 403, within the MYH7 VCEP PM1 interval of codons 167-931, with HCM clinical reports.
cspec PMID:1975517 PMID:1638703 PMID:12975413
PM2 Met Met at Supporting: European (non-Finnish) gnomAD v4.1 has AC=1 in AN=1,180,040, satisfying the VCEP PM2 equivalent AC≤1 in AN≥120,000 condition.
cspec gnomad_v4 gnomad_v2
PM3 N/A Not applicable: the MYH7 VCEP excludes recessive PM3 use from this autosomal-dominant cardiomyopathy guideline.
cspec
PM4 N/A Not applicable: PM4's VCEP rule names deletions/insertions or non-NMD truncating variants, whereas this is a p.Arg403Gln missense substitution.
cspec
PM5 Not met Not met: the comparator collection found 0 same-residue candidates for codon 403, so no qualifying different missense variant supports PM5.
cspec pm5_candidates PMID:1975517 PMID:1638703 PMID:12975413
PM6 Not assessed Not assessed: one ClinVar submission reports de novo origin without parental confirmation, but phenotype consistency and the required case evidence are undocumented.
cspec clinvar
PP1 Met Met at strong: 20 affected Arg403Gln family members were reported across two families, exceeding the VCEP threshold of at least 7 segregations.
cspec PMID:12975413 PMID:1638703 PMID:1975517
PP2 N/A Not applicable: the MYH7 VCEP explicitly excludes PP2 and directs regional rare-missense enrichment to PM1.
cspec
PP3 Met Met: REVEL 0.886 meets the VCEP PP3 threshold of >=0.70 for this missense variant.
cspec revel spliceai
PP4 N/A Not applicable: the MYH7 VCEP excludes PP4 because inherited cardiomyopathies have high locus heterogeneity and non-genetic etiologies.
cspec
PP5 Met Not applicable: the MYH7 VCEP prohibits PP5 under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.
cspec clinvar
BA1 Not assessed Not assessed: BA1 requires popmax FAF ≥0.001, but only observed AF 8.47429e-07 (1/1,180,040 alleles) is available.
cspec gnomad_v4
BS1 Not assessed Not assessed: BS1 requires popmax FAF ≥0.0001, but only observed AF 8.47429e-07 (1/1,180,040 alleles) is available.
cspec gnomad_v4
BS2 N/A Not applicable: the MYH7 VCEP marks BS2 Not applicable because inherited cardiomyopathies have reduced penetrance, variable expressivity, and adult onset.
cspec
BS3 Not assessed Not assessed: no verified controlled assay demonstrates that p.Arg403Gln has no damaging effect on MYH7 function or splicing.
cspec
BS4 Not met Not met: no qualifying affected non-carriers are reported, while one 9-month-old carrier was phenotype-negative and does not constitute a BS4 non-segregation.
cspec PMID:1638703 PMID:12975413 PMID:1975517
BP1 N/A Not applicable: the MYH7 VCEP excludes BP1 because pathogenic missense variants are reported despite the known null-variant mechanism.
cspec
BP2 Not assessed Not assessed: no documented pathogenic partner, cis/trans phase, or two qualifying cases are available for the required BP2 comparison.
cspec
BP3 N/A Not applicable: the MYH7 VCEP v2.0 entry explicitly marks BP3 Not Applicable for this p.Arg403Gln missense variant.
cspec
BP4 Not met Not met: REVEL 0.886 is above the VCEP BP4 threshold of <=0.40, despite SpliceAI's maximum delta score of 0.018.
cspec revel spliceai
BP5 N/A Not applicable: the MYH7 VCEP excludes BP5 because an alternate non-cardiomyopathy diagnosis does not reduce independent cardiomyopathy causation.
cspec
BP6 N/A Not applicable: the MYH7 VCEP prohibits BP6 under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.
cspec
BP7 N/A Not applicable: c.1208G>A is an exon 13 missense variant, whereas VCEP BP7 covers only qualifying intronic variants.
cspec
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