NM_000143.4:c.301C>T (p.Arg101Ter) is a nonsense variant in exon 3 of 10 in the FH gene, which encodes fumarate hydratase. Loss-of-function variants in FH are an established cause of autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC).¹ This variant introduces a premature termination codon at position 101 of 511 amino acids, predicted to trigger nonsense-mediated decay and result in complete loss of protein function. Under ClinGen SVI PVS1 guidelines, this meets criteria for PVS1 at very strong strength.² The variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present at extremely low frequency in gnomAD v4.1 (12/1,613,900 alleles, AF = 0.00074%, no homozygotes), meeting PM2 at moderate strength.³ Protein-truncating FH mutations have been demonstrated to be functionally null alleles in published studies, and OncoKB annotates R101* as Likely Loss-of-function, supporting a damaging functional effect at PS3 supporting strength.⁴ This variant has been classified as Pathogenic by 14 clinical laboratories in ClinVar (Variation ID 16232) and is annotated as Likely Oncogenic by OncoKB, meeting PP5 at supporting strength.⁵ No benign criteria are met. The variant is absent or at extremely low frequency in population databases (BA1/BS1 not met), functional evidence supports a damaging effect (BS3 not met), and no reputable source reports this variant as benign (BP6 not met).⁶ Applying the ACMG/AMP 2015 combination rules: 1 Very Strong (PVS1) + 1 Moderate (PM2) + 2 Supporting (PS3, PP5) satisfies the threshold for Pathogenic classification.⁷