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).

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.

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.

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.

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.

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).

Applying the ACMG/AMP 2015 combination rules: 1 Very Strong (PVS1) + 1 Moderate (PM2) + 2 Supporting (PS3, PP5) satisfies the threshold for Pathogenic classification.