NM_000257.3:c.2548G>A (p.Ala850Thr) is a missense variant in MYH7 exon 22. It is extremely rare in population databases (gnomAD v2.1 AF 3.98e-6, v4.1 grpmax FAF 7.9e-7), satisfying VCEP PM2 at supporting strength.¹ Codon 850 falls within the VCEP-defined MYH7 missense cluster region (codons 167-931), meeting PM1 at moderate strength per Walsh et al. 2019 (PMID:30696458).² REVEL in silico meta-predictor score is 0.809, exceeding the VCEP PP3 threshold of ≥0.70, providing supporting evidence for a deleterious effect. SpliceAI predicts no splice impact.³ A sister missense variant at the same codon, p.Ala850Asp, was reported as a novel mutation in one HCM patient by Fokstuen et al. 2008 (PMID:18409188), but lacks formal VCEP classification necessary for PM5 application.⁴ No functional studies, segregation data, de novo observations, or case-control data were identified for this specific variant in any reviewed publication. The variant has been reported in ClinVar (ID 403207) as Uncertain Significance by 5 clinical laboratories and Likely Pathogenic by 1 (Invitae). No expert panel classification has been assigned. ClinVar review status is 'criteria provided, single submitter' at the aggregate level.⁵ Applying the MYH7 VCEP v2.0 classification rules: 1 moderate criterion (PM1) and 2 supporting criteria (PM2_Supporting, PP3) are met. This combination does not satisfy any VCEP Likely Pathogenic rule (minimum: Rule 14 requires 2 moderate + ≥2 supporting; Rule 15 requires 1 moderate + ≥4 supporting). The variant remains a Variant of Uncertain Significance.⁶