Variant classification summary

NM_000410.4:c.187C>G

HFE · NP_000401.1:p.(His63Asp) · NM_000410.4

GRCh37: chr6:26091179 C>G · GRCh38: chr6:26090951 C>G

Gene: HFE Transcript: NM_000410.4

Final call

VUS

PS3 supporting

Variant details

Gene

HFE

Transcript

NM_000410.4

Protein

NP_000401.1:p.(His63Asp)

gnomAD AF

0.131951957310809 (v4.1)

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PS3 supporting functional evidence showed impaired HFE-mediated iron handling in THP-1 cells and macrophages.

2

VUS: No additional pathogenic or benign criterion is met, so no generic ACMG/AMP definitive combination rule is satisfied.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one supporting pathogenic criterion alone satisfies no pathogenic or benign combination, so the final call is VUS.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic HFE variant with the same His63Asp amino-acid change but a different nucleotide change was documented.	pm5_candidates
PS2	Not assessed	Not assessed: no documented proband de novo event with both maternity and paternity confirmed.	PMID:11358905 PMID:28617828
PS3	Met	Met at supporting: H63D lost HFE-mediated inhibition of iron release in THP-1 cells and macrophages, with wild-type, mutant, and iron-handling controls.	PMID:12429850 PMID:28617828
PS4	Not assessed	Not assessed: no verified case-control odds ratio or relative risk was available to test the PS4 requirement of >5.0 with a confidence interval excluding 1.0.	gnomad_v4 PMID:11358905 PMID:16132052 PMID:28617828 PMID:8696333
PM1	Not met	Not met: H63D lacks documented critical-domain evidence, and Cancer Hotspots found no statistically significant hotspot; COSMIC reported 12 somatic occurrences.	hotspots cosmic
PM2	Not met	Not met: gnomAD v4.1 reports AF 13.20% and 15,277 homozygotes, far above the PM2 threshold of 0.01%.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: compound heterozygosity is reported, but parent or offspring testing confirming phase for the H63D/C282Y observations is not documented.	PMID:16132052
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: the comparator collection found zero HFE residue-63 candidates but did not provide a complete verified search for a different pathogenic missense change.	pm5_candidates
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence in a clinically characterized patient.	PMID:11358905 PMID:28617828
PP1	Not assessed	Not assessed: no qualifying count of multiple affected relatives carrying the variant is documented.	PMID:11358905 PMID:28617828
PP2	Not met	Not met: HFE H63D has gnomAD v4.1 allele frequency 0.131952 with 15,277 homozygotes, inconsistent with low benign missense variation.	gnomad_v4 PMID:16132052
PP3	Not met	Not met: missense REVEL score 0.315 is below the PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not provided, so specificity for a single genetic etiology cannot be judged.	PMID:11358905 PMID:16132052
PP5	Not met	Not met: ClinVar reports 0 expert-panel submissions for the exact variant, so laboratory and aggregate Pathogenic labels cannot trigger PP5.	clinvar
BA1	Not assessed	Not assessed: gnomAD v4.1 grpmax FAF is 14.96% versus the 5% BA1 threshold, but HFE H63D is a documented reduced-penetrance disease-associated allele.	gnomad_v4 gnomad_v2 PMID:11358905 PMID:16132052
BS1	Not assessed	Not assessed: gnomAD v4.1 grpmax FAF is 14.96% versus the 1% BS1 default, but HFE H63D has reduced and variable penetrance requiring disease-specific modeling.	gnomad_v4 gnomad_v2 PMID:11358905 PMID:16132052
BS2	Not assessed	Not assessed: gnomAD reports 15,277 H63D homozygotes, but individual healthy-adult status and full early-onset penetrance are not established.	gnomad_v4 gnomad_v2 PMID:11358905 PMID:16132052
BS3	Not met	Not met: H63D lost HFE-mediated iron-release inhibition in THP-1 cells and macrophages rather than showing preserved protein function or splicing.	PMID:12429850
BS4	Not assessed	Not assessed: no confirmed affected relative lacking the variant is documented in a qualifying pedigree.	PMID:28617828
BP1	Not met	Not met: HFE disease literature centers on missense C282Y and H63D alleles, not primarily truncating variants.	PMID:16132052 PMID:11358905
BP2	N/A	Not applicable: the reported H63D/C282Y relationship is trans in a recessive HFE disorder, whereas BP2 requires dominant trans or any-inheritance cis evidence.	PMID:16132052
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.315 exceeds the BP4 supporting threshold of 0.29 and is not a benign-range result.	revel
BP5	Not assessed	Not assessed: no alternate molecular diagnosis is documented for the patient carrying NM_000410.4:c.187C>G.	PMID:11358905 PMID:28617828
BP6	Not met	Not met: ClinVar reports 0 expert-panel submissions and no exact-variant expert-panel Benign or Likely benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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