NM_000143.4:c.151C>T

FH · NP_000134.2:p.(Arg51Trp) · NM_000143.4

GRCh37: chr1:241680598 G>A · GRCh38: chr1:241517298 G>A

Gene: FH Transcript: NM_000143.4

Final call

VUS

PS3 supporting PM2 moderate PP3 supporting

Variant details

Gene

Transcript

NM_000143.4

Protein

NP_000134.2:p.(Arg51Trp)

gnomAD AF

2.4783792391127897e-06 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This missense variant (c.151C>T, p.Arg51Trp) is extremely rare in population databases (gnomAD v2.1 allele frequency 0.00080%, v4.1 allele frequency 0.00025%), meeting PM2 at moderate strength.

In one patient with pheochromocytoma, tumor tissue analysis revealed loss of heterozygosity at the FH locus and positive 2-SC immunostaining confirming FH deficiency, providing functional evidence at supporting strength (PS3_supporting).

Multiple in silico tools predict a deleterious effect (REVEL score 0.799), supporting a pathogenic role at the protein level (PP3_supporting).

The variant has been reported in ClinVar (VariationID 649446) as Likely pathogenic by multiple clinical laboratories (4 LP, 1 P, 1 VUS), but no expert panel review is available; PP5 is not met.

PVS1 is not applicable as this is a missense variant. PS4 is not met due to insufficient published case numbers. Remaining pathogenic and benign criteria are not met.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	This is a missense substitution (c.151C>T, p.Arg51Trp); PVS1 applies to null variants (nonsense, frameshift, canonical splice site) and this variant does not fall into those buckets.	pvs1_variant_assessment
PS1	Not met	No evidence of a different nucleotide change at c.151 predicted to produce the same amino acid substitution (p.Arg51Trp).
PS2	Not met	No de novo report for NM_000143.4:c.151C>T was identified in the available literature or ClinVar submissions.
PS3	Met	In one patient with pheochromocytoma, PCC tissue analysis of this variant revealed loss of heterozygosity at the FH locus and positive 2-SC (S-(2-succinyl)cysteine) immunostaining, confirming FH deficiency in the tumor and supporting a deleterious functional effect.	PMID:30877234
PS4	Not met	Only one published case with variant-specific clinical detail (PCC at age 55, PMID 30877234). Insufficient case numbers to establish statistically significant enrichment over population controls. Additional cases may exist in clinical laboratory internal data but are not publicly accessible.	PMID:30877234 clinvar
PS5	Not met	No different pathogenic variant at the same codon (Arg51) was identified from a clinically validated source.
PM1	Not met	Residue 51 is located in the N-terminal Domain 1 of FH (residues 49-188), which is a structural domain without a characterized independent functional role. The variant does not fall within the fumarate lyase domain (exons 5-7) and is not in a statistically significant mutational hotspot per cancerhotspots.org.	PMID:30761759
PM2	Met	This variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 7.96e-06 (0.00080%, 2/251,290 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency is 2.48e-06 (0.00025%, 4/1,613,958 alleles, 0 homozygotes). Both are well below the 0.1% PM2 threshold for a rare disease gene.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue comparator variant with a different pathogenic amino acid change was identified. Automated PM5 candidate harvesting did not identify eligible comparators.	pm5_candidates
PM6	Not met	No de novo report for this variant was identified in the available literature or ClinVar submissions.
PP1	Not met	No co-segregation data available. The only published case (PMID 30877234) provides no family segregation information.
PP2	Not met	Although missense variants are the most common mutation type in FH (55%), there is insufficient evidence that the rate of benign missense variants in FH is low enough to satisfy PP2 under generic ACMG.	PMID:30761759
PP3	Met	Multiple in silico tools predict a deleterious effect: REVEL score of 0.799 is in the pathogenic range. SpliceAI predicts no splice impact (max delta = 0.00), so the predicted effect is at the protein level.	revel spliceai bayesdel
PP4	Not met	Pheochromocytoma alone is not a highly specific phenotype for FH-related disease; it is associated with multiple other genes (SDHx, VHL, RET, NF1, etc.). The patient phenotype does not meet the threshold for PP4.	PMID:30877234
PP5	Not met	ClinVar review status for this variant (VariationID 649446) is 'criteria provided, single submitter' with 0 expert panel submissions. PP5 requires ClinVar classification reviewed by expert panel (3-star) to apply at supporting strength.	clinvar
BA1	Not met	gnomAD allele frequency (0.00080% v2.1, 0.00025% v4.1) is far below the 1% BA1 threshold for standing as a benign variant.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency (0.00080%) is below the 0.3% BS1 threshold for a variant too common to cause a rare disease.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations in gnomAD. No evidence of the variant being observed in a healthy adult individual in trans with a known pathogenic FH variant.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this variant. The only available functional evidence (PMID 30877234) points toward pathogenicity (LOH + positive 2-SC staining).	PMID:30877234
BS4	Not met	No evidence of non-segregation with disease in affected families.
BP1	Not met	BP1 applies to missense variants in genes where only truncating variants cause disease. FH has numerous well-established pathogenic missense variants (missense mutations represent 55% of reported variants). BP1 is not applicable.	PMID:30761759
BP2	Not met	No observation of this variant in trans with a known pathogenic FH variant.
BP4	Not met	Multiple in silico tools predict a deleterious effect (REVEL 0.799). SpliceAI predicts no splice impact (max delta = 0.00), but protein-level predictions contradict BP4. BP4 is not met when computational evidence supports pathogenicity.	revel spliceai bayesdel
BP5	Not met	No strong evidence from other sources suggesting a benign role. The variant has been observed in a case with PCC and is absent from large population cohorts at significant frequency.
BP6	Not met	ClinVar review status for this variant is 'criteria provided, single submitter' with 0 expert panel submissions. BP6 requires a 3-star expert panel classification of benign or likely benign.	clinvar
BP7	Not met	This is a missense variant (c.151C>T, p.Arg51Trp), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	Variant is a substitution; BP3 applies to in-frame deletions/insertions in repetitive regions.
PM3	N/A	FH-related disease (HLRCC) is autosomal dominant; PM3 applies to recessive disorders only.
PM4	N/A	Variant is a missense substitution; PM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss).

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.