The HFE NM_000410.4:c.187C>G (NP_000401.1:p.(His63Asp)) missense variant has previously been reported in somatic cancers (COSMIC; COSV58513169, n = 12 times). Experimental evidence: H63D lost HFE-mediated inhibition of iron release in THP-1 cells and macrophages, with wild-type, mutant, and iron-handling controls. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.HFE encodes a cell-surface protein that helps regulate the body’s iron absorption by influencing how transferrin interacts with its receptor. Inherited changes in HFE can cause hereditary hemochromatosis, a disorder in which the body stores too much iron. HFE can also be altered in cancer, and inherited HFE changes may increase the risk of some cancers.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
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.
No benign criterion marked as applied in the recorded assessment.
VUS: PS3 at supporting strength is the only applied criterion, and generic ACMG/AMP rules require stronger or multiple evidence combinations for a definitive call.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 212,957 / 1,613,898 alleles. Recorded AF 0.131952. Recorded homozygote count 15277.
This variant is present in gnomAD v2.1 (AF= 0.108159; MAF= 10.81586%, 30592/282844 alleles, homozygotes = 2023) and has highest observed frequency in the European (non-Finnish) population (AF= 0.144269; MAF= 14.42695%, 18635/129168 alleles, homozygotes = 1432); grpmax FAF= 0.142294.
This variant is present in gnomAD-Canada v1.0 (AF= 0.13504997827031726, 2486/18408 alleles, homozygotes = 196).
Recorded REVEL score: 0.315. Refer to the recorded PP3/BP4 rationale for interpretation.
46 Pathogenic · 3 Uncertain significance · 1 Likely pathogenic · 1 other · 1 Pathogenic, low penetrance · 1 likely pathogenic · 1 Benign. ClinVar API review status: criteria provided, conflicting classifications.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. HFE, a transmembrane protein, is altered by mutation in various cancers. Germline HFE mutations are associated with hemochromatosis and predispose to
This variant has previously been reported in somatic cancers (COSMIC; COSV58513169, n = 12 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 9 not met · 13 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
None of PS2, PM6, PP1, or BS4 is assessable from the available proband, parental, pedigree, and segregation evidence.
The available HFE H63D literature describes cohort or disease-context observations but does not provide the specific family data required for these criteria.
Both criteria were assessed on the missense-specific REVEL path. REVEL 0.315 is below the PP3 supporting cutoff of 0.644 and above the BP4 supporting cutoff of 0.29; neither criterion is met.
No criteria match.
PS3 is met at supporting strength. The exact HFE H63D variant, corresponding to NM_000410.4:c.187C>G, was tested in a controlled functional study using THP-1 cells and ex vivo CD68-positive macrophages. Relative to wild-type HFE, H63D (reported as H41D using mature-protein numbering) retained transferrin-receptor binding but lost the ability to inhibit iron release and failed to increase ferritin or reduce TfR1 in THP-1 cells. The study included wild-type, binding-deficient V78A, other HFE mutants, control vaccinia, iron-loading and iron-chelation controls, and replicated release measurements, providing biologically relevant evidence of impaired HFE function. The evidence is not upgraded because the study was not shown to be validated and reproducible in a clinical diagnostic laboratory setting, and the additional H63D study in an alpha-1-antitrypsin-deficiency model evaluates a context-dependent modifier phenotype rather than a validated core HFE assay.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
HFE has no retrieved VCEP specification or approved domain table. The H63D variant is not supported by the supplied evidence as lying in a well-established critical functional domain without benign variation, and Cancer Hotspots returned no statistically significant hotspot. COSMIC reports the variant 12 times in somatic cancers, but this generic assessment does not establish a qualifying hotspot or critical-domain route.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is not met because the variant is common in population controls. Using the default all-comers datasets because no VCEP specifies a different source, gnomAD v4.1 reports AF=0.131952 with 212957/1613898 alleles and 15277 homozygotes, while gnomAD v2.1 reports AF=0.108159 with 30592/282844 alleles and 2023 homozygotes. These frequencies are far above the generic PM2 supporting threshold of <=0.0001; non-cancer subsets independently confirm common occurrence.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
HFE disease can involve missense variation, but the supplied evidence does not support a low rate of benign missense variation. H63D itself is common in population data, with gnomAD v4.1 allele frequency 0.131952 and 15,277 homozygotes; a review describes H63D as approximately 2% in European countries and rarely associated with iron loading.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The variant is a missense SNV, so the governing generic rule requires the missense REVEL path only; SpliceAI and BayesDel are not used for PP3 in this situation. REVEL is 0.315, below the generic PP3 supporting threshold of >= 0.644, so PP3 is not met. The REVEL threshold is from the supplied ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997).
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)...Missense variant -> REVEL only...PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
PP5 is not met because the exact-variant ClinVar record has zero expert-panel submissions. The available Pathogenic and Likely pathogenic assertions are ordinary laboratory submissions or aggregate labels, which do not satisfy the required reputable-source expert-panel condition for this criterion.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BS3 is not met. The strongest directly relevant functional evidence does not show a lack of damaging effect: HFE H63D/H41D retained transferrin-receptor binding but lost the ability to inhibit iron release and failed to produce wild-type iron-handling responses in THP-1 cells and ex vivo macrophages. The reviewed functional studies therefore support impaired rather than normal HFE activity, and no well-established assay demonstrating no damaging effect on HFE protein function or splicing was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP1 does not apply because HFE is not a gene for which primarily truncating variants are known to cause disease. The reviewed HFE literature identifies the common missense variants C282Y and H63D as the principal disease-associated alleles, with H63D-associated phenotypes generally milder or context dependent.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense SNV, so the governing generic rule requires the missense REVEL path only; the SpliceAI no-impact result cannot substitute for REVEL. REVEL is 0.315, above the generic BP4 supporting threshold of <= 0.29 and therefore in the gray zone rather than supporting no impact, so BP4 is not met. The REVEL threshold is from the supplied ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997).
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)...Missense variant -> REVEL only...BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP6 is not met because the exact-variant ClinVar record has zero expert-panel submissions and no exact-variant expert-panel benign or likely benign classification. The single ordinary Benign laboratory submission and aggregate ClinVar labels are insufficient under the stated BP6 restriction.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is HFE p.His63Asp (c.187C>G), but the supplied evidence does not establish a previously pathogenic HFE variant producing the same amino-acid change through a different nucleotide change. The exact H63D variant's ClinVar submissions and H63D literature cannot substitute for the required alternate-nucleotide comparison. A complete codon-level comparison against established pathogenic variants is still needed.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No proband-level de novo observation with confirmed maternity and paternity was identified. The available evidence does not document parental genotypes, a family history assessment, or a disease-affected proband in a way that permits application of PS2.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No verified case-control comparison with affected and unaffected/population counts, odds ratio, relative risk, or confidence interval was identified for NM_000410.4:c.187C>G. The reviewed H63D literature includes phenotype observations and population statements, but does not provide the required variant-specific estimate demonstrating OR/RR >5.0 with a confidence interval excluding 1.0. The variant is common in gnomAD v4.1 (AF 0.131952; European non-Finnish AF 0.150159), but population frequency alone is not a PS4 case-control comparison. The literature-pass PS4 candidate list was checked against the available abstracts/full-text extracts; the available materials do not supply the required case-control counts or estimate.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 cannot be assessed from the available evidence. PMID:16132052 reports that the HFE C282Y/H63D compound-heterozygous genotype occurred in affected haemochromatosis patients and describes H63D as being on chromosomes not carrying C282Y, which is consistent with the H63D variant being in trans with C282Y. However, the report is a review of prior genotype/phenotype studies and does not document parent or offspring testing for the specific observations, as required to establish phase under the governing rule; it also does not provide a case-level count with documented parental or offspring phase. Therefore, the available evidence does not satisfy the required phase documentation for PM3.
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The supplied PM5 comparator collection contains zero same-residue candidates, but it also states that classic PM5 semantics could not be confirmed safely and that automatic candidate harvesting was skipped. Therefore, the evidence does not establish whether a different pathogenic missense variant has been observed at HFE residue 63. A verified same-residue pathogenic-variant search remains necessary.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No assumed de novo occurrence in a patient was identified. The available evidence does not document a proband, disease phenotype, or parental testing status sufficient to establish an assumed de novo event without maternity and paternity confirmation.
Assumed de novo, but without confirmation of paternity and maternity.
No documented pedigree shows the variant co-segregating with disease in multiple affected family members. PMID:11358905 is a cohort of H63D homozygotes without the required family segregation data, and PMID:28617828 reports affected and unaffected family members in a different Alpha-1-Antitrypsin Deficiency context without a qualifying multi-affected-relative segregation analysis.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The case materials do not provide the patient's clinical phenotype, family history, or a disease-specific presentation. Published H63D cohorts describe variable iron-related phenotypes, but those cohort observations cannot substitute for a phenotype assessment in this case or establish that the phenotype is highly specific for a single genetic etiology.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The default BA1 frequency threshold is exceeded: gnomAD v4.1 all-comers has grpmax FAF 0.149571 and gnomAD v2.1 has grpmax FAF 0.142294, both above 0.05, with qualifying population allele counts well above 2000. However, this is HFE p.His63Asp (H63D), a well-documented common, reduced-penetrance hemochromatosis-associated allele; ClinVar contains 46 Pathogenic submissions and a Pathogenic, low penetrance submission, and published review evidence describes an estimated European frequency of 2% and rare iron-loading disease in H63D homozygotes. Because the high frequency conflicts with the pathogenic/low-penetrance disease association, the generic frequency default alone is insufficient for a stand-alone benign BA1 call.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The population frequency is far above the generic BS1 default: gnomAD v4.1 all-comers grpmax FAF is 0.149571 and gnomAD v2.1 grpmax FAF is 0.142294, both above 0.01, with qualifying population allele counts above 2000. Nevertheless, BS1 asks whether the frequency is greater than expected for the disorder, and HFE H63D has documented reduced penetrance, late/variable expression, and a strong pathogenic/low-penetrance clinical association. No disease-specific maximum credible allele frequency calculation with prevalence, penetrance, and allelic heterogeneity inputs is available, so the 1% default cannot be used alone.
Allele frequency is greater than expected for the disorder.
gnomAD documents many HFE H63D homozygotes, including 15277 homozygotes in gnomAD v4.1 all-comers and 2023 in gnomAD v2.1, but these aggregate population records do not establish that any specific individual was a healthy adult with the relevant phenotype excluded, nor do they establish full early-age penetrance for the disorder. Published evidence instead documents variable and reduced penetrance in H63D homozygotes. Therefore the BS2 healthy-adult requirement cannot be confirmed from the available evidence.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No affected family member is documented as lacking the variant in a pedigree suitable for assessing non-segregation. The report in PMID:28617828 concerns HFE H63D association with liver damage in Alpha-1-Antitrypsin Deficiency and includes unaffected siblings, but the extracted evidence does not establish affected relatives who are confirmed variant-negative for the disease under evaluation; therefore BS4 cannot be applied.
Lack of segregation in affected members of a family.
No case-specific evidence identifies the variant in a patient with an alternate molecular basis for disease. Published HFE and H63D observations do not establish an alternate molecular diagnosis for this case, and no such diagnosis is documented in the available case materials.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000410.4:c.187C>G in HFE is a missense substitution predicted to produce NP_000401.1:p.(His63Asp). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for HFE, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000410.4:c.187C>G in HFE is a missense substitution predicted to produce NP_000401.1:p.(His63Asp). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for HFE, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP2 is not applicable to the available allelic observation. The relevant source describes HFE H63D in compound heterozygosity with C282Y, consistent with a trans configuration, but BP2 requires either a trans observation in a fully penetrant dominant gene/disorder or a cis observation with a pathogenic variant in any inheritance pattern. HFE hereditary haemochromatosis is treated here as a recessive disorder under the PM3 framework, and no cis observation or fully penetrant dominant HFE disorder is documented.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000410.4:c.187C>G in HFE is a missense substitution predicted to produce NP_000401.1:p.(His63Asp). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for HFE, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000410.4:c.187C>G in HFE is a missense substitution predicted to produce NP_000401.1:p.(His63Asp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for HFE, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in HFE, mapped onto the exon structure of NM_000410.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)177167 / 1,179,864 | 0.1513363 hom |
| Remaining individuals7811 / 62,498 | 0.12513 hom |
| Middle Eastern736 / 6,062 | 0.1256 hom |
| Ashkenazi Jewish3458 / 29,600 | 0.12216 hom |
| Admixed American6293 / 60,016 | 0.1355 hom |
| European (Finnish)6665 / 64,000 | 0.1339 hom |
| South Asian7232 / 91,080 | 0.079378 hom |
| Amish66 / 912 | 0.0721 hom |
| East Asian1379 / 44,872 | 0.03121 hom |
| African/African American2150 / 74,994 | 0.02935 hom |
| European (non-Finnish)18635 / 129,168 | 0.141432 hom |
| Remaining individuals872 / 7,222 | 0.1255 hom |
| Ashkenazi Jewish1113 / 10,370 | 0.1160 hom |
| European (Finnish)2598 / 25,118 | 0.1137 hom |
| Admixed American3556 / 35,438 | 0.1203 hom |
| South Asian2457 / 30,616 | 0.08115 hom |
| East Asian680 / 19,952 | 0.03411 hom |
| African/African American681 / 24,960 | 0.02710 hom |
This variant is present in gnomAD v4.1 (AF= 0.131952; MAF= 13.19520%, 212957/1613898 alleles, homozygotes = 15277) and has highest observed frequency in the European (non-Finnish) population (AF= 0.150159; MAF= 15.01588%, 177167/1179864 alleles, homozygotes = 13363); grpmax FAF= 0.149571.
This variant is present in gnomAD v2.1 (AF= 0.108159; MAF= 10.81586%, 30592/282844 alleles, homozygotes = 2023) and has highest observed frequency in the European (non-Finnish) population (AF= 0.144269; MAF= 14.42695%, 18635/129168 alleles, homozygotes = 1432); grpmax FAF= 0.142294.
This variant is present in gnomAD-Canada v1.0 (AF= 0.13504997827031726, 2486/18408 alleles, homozygotes = 196).
The variant is a missense SNV, so the governing generic rule requires the missense REVEL path only; SpliceAI and BayesDel are not used for PP3 in this situation. REVEL is 0.315, below the generic PP3 supporting threshold of >= 0.644, so PP3 is not met. The REVEL threshold is from the supplied ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997).
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)...Missense variant -> REVEL only...PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense SNV, so the governing generic rule requires the missense REVEL path only; the SpliceAI no-impact result cannot substitute for REVEL. REVEL is 0.315, above the generic BP4 supporting threshold of <= 0.29 and therefore in the gray zone rather than supporting no impact, so BP4 is not met. The REVEL threshold is from the supplied ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997).
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)...Missense variant -> REVEL only...BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000410.4:c.187C>G in HFE is a missense substitution predicted to produce NP_000401.1:p.(His63Asp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for HFE, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.315. BayesDel score = -0.0676057.
10 paper records listed. 2 cited in the classification.
Three HFE mutants, H41D (which is associated with HH; ref. 3), R44E and W141A, which all bind TfR1 with WT affinity (5), retain the ability to make U937 cells iron-deficient, but lose the ability to increase ferritin and reduce TfR1 on THP-1 cells. Fig. 3 B and C show that H41D and V78A have lost the ability to block iron release, and W141A and R44E have reduced ability to block iron release from THP-1 cells compared with WT HFE. ... The results with the HFE mutants show that V78A abolishes both binding to TfR1 and inhibition of iron release, whereas H41D, R44E, and W141A have no effect on binding to TfR1, but abolish or reduce the inhibitory effect on iron release.
Location Results, ‘Effects of Various HFE Mutants on THP-1 Cells, U937 Cells, and ex Vivo Macrophages,’ paragraphs 2–3
Context In vitro THP-1 and U937 monocyte-cell assays and ex vivo CD68-positive macrophage iron-release assays using wild-type HFE, HFE mutants, control vaccinia, iron-loading and iron-chelation controls; 59Fe uptake and release measurements were used, with release assays performed in triplicate where specified.
Whole exome sequencing of 1ATD patients resulted in the identification of two variants associated with liver damages in Z-1AT homozygous cases: HFE H63D and HERPUD1 R50H. Functional characterization in Z-1AT model cell lines demonstrated that impairment of the ERAD machinery combined with the HFE H63D variant expression decreased both cell proliferation and cell viability, while Unfolded Protein Response (UPR)-mediated cell death was hyperstimulated.
Location Abstract; Results, ‘Exome sequencing and functional studies’; Table 1 and its footnote
Context Whole-exome sequencing of five small families containing individuals homozygous for the Z-1AT allele, comparing ZZ individuals with and without liver abnormalities; functional studies in Z-1AT model cell lines assessing cell proliferation, viability, and UPR-mediated responses under impaired ERAD conditions.
No additional mutation of HFE was identified.
Abstract, Results; Results, “Sequence analysis of the HFE gene”; Table 3
Despite an estimated frequency of 2% in European countries, the H63D homozygous genotype is rarely associated with an iron-loading condition. Moreover, the H63D amino-acid change has little effect on HFE protein structure and is not expected to produce a significant loss-of-function.
Haemochromatosis type 1 – HFE related; subsection “Predominance of the C282Y homozygous and C282Y/H63D compound heterozygous genotypes in the haemochromatosis patients,” paragraphs 1–2
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.131952; MAF= 13.19520%, 212957/1613898 alleles, homozygotes = 15277) and has highest observed frequency in the European (non-Finnish) population (AF= 0.150159; MAF= 15.01588%, 177167/1179864 alleles, homozygotes = 13363); grpmax FAF= 0.149571.
This variant is present in gnomAD v2.1 (AF= 0.108159; MAF= 10.81586%, 30592/282844 alleles, homozygotes = 2023) and has highest observed frequency in the European (non-Finnish) population (AF= 0.144269; MAF= 14.42695%, 18635/129168 alleles, homozygotes = 1432); grpmax FAF= 0.142294.
This variant is present in gnomAD-Canada v1.0 (AF= 0.13504997827031726, 2486/18408 alleles, homozygotes = 196).
This variant has been reported in ClinVar as Pathogenic (46 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as other (1 clinical laboratory) and as Pathogenic, low penetrance (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 10)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.315. BayesDel score = -0.0676057.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. HFE, a transmembrane protein, is altered by mutation in various cancers. Germline HFE mutations are associated with hemochromatosis and predispose to
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58513169, n = 12 times).
This variant does not lie in a statistically significant hotspot.