The HFE NM_000410.4:c.845G>A (NP_000401.1:p.(Cys282Tyr)) missense variant has previously been reported in somatic cancers (COSMIC; COSV107360943, n = 1 time). Experimental evidence: Independent cellular and mouse studies showed loss of beta-2-microglobulin interaction, absent surface expression, and altered HFE-dependent phenotypes for C282Y. 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 strong strength: the identical p.Cys282Tyr change accounts for more than 80% of Caucasian hemochromatosis cases in the cited cohort summary.
Met, strong: independent cellular and mouse studies showed loss of beta-2-microglobulin interaction, absent surface expression, and altered HFE-dependent phenotypes for C282Y.
Met at moderate strength: REVEL 0.872 exceeds the generic PP3 moderate threshold of 0.773 for missense variants.
Met: gnomAD v4.1 all-comers allele frequency is 0.0569823, exceeding the >=0.05 BA1 stand-alone threshold.
VUS: PS1 (strong) plus PS3 (strong) satisfies a pathogenic rule, while BA1 independently satisfies the benign stand-alone rule under generic ACMG/AMP criteria.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 91,977 / 1,614,134 alleles. Recorded AF 0.0569823. Recorded homozygote count 3399.
This variant is present in gnomAD v2.1 (AF= 0.0337712; MAF= 3.37712%, 9544/282608 alleles, homozygotes = 276) and has highest observed frequency in the European (non-Finnish) population (AF= 0.057658; MAF= 5.76580%, 7435/128950 alleles, homozygotes = 243); grpmax FAF= 0.056289.
This variant is present in gnomAD-Canada v1.0 (AF= 0.03758010209623113, 692/18414 alleles, homozygotes = 14).
Recorded REVEL score: 0.872. Refer to the recorded PP3/BP4 rationale for interpretation.
43 Pathogenic · 2 Uncertain significance · 1 risk factor · 1 other · 1 Pathogenic, low penetrance · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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; COSV107360943, n = 1 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: 4 met · 8 not met · 12 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Variant-specific functional evidence is concordantly damaging across an orthogonal human-cell trafficking assay, a human-cell phenotype assay, and a homologous in vivo mouse model.
No variant-specific functional evidence supports preserved HFE function or normal splicing for BS3.
No VCEP covers HFE, so generic ACMG/AMP 2015 definitions govern.
PS4 was not met because no qualifying exact-variant affected-versus-control prevalence data support OR >5.0 with a confidence interval excluding 1.0.
PP5 and BP6 were restricted to exact-variant ClinVar expert-panel classifications; the audit reports none.
Population evidence supports BA1 because the all-comers gnomAD v4.1 allele frequency is 0.0569823, above 0.05.
BS1 is not assessed because the generic 1% default is insufficient for this ancestry-enriched, reduced-penetrance allele without a maximum-credible-frequency calculation.
BS2 and PM2 are not met: population homozygote counts do not establish the BS2 healthy-adult condition, and the allele is far above the PM2 rarity threshold.
No criteria match.
NM_000410.4:c.845G>A produces p.Cys282Tyr (C282Y), and this same amino-acid change is explicitly reported in affected individuals with HFE-related hemochromatosis. PMID:27518069 states that more than 80% of Caucasian hemochromatosis cases are related to C282Y homozygosity; PMID:10575540 reports C282Y in hemochromatosis probands with iron overload. These reports establish the same p.Cys282Tyr change as pathogenic at the protein level, with no evidence in the reviewed extracts that the observation is driven by a splicing effect.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PS3 is met at strong strength. The exact HFE C282Y variant was tested in independent, biologically relevant functional systems with wild-type and comparator controls. In HEK293 cells, C282Y abolished beta-2-microglobulin interaction, eliminated detectable cell-surface expression, and caused intracellular/perinuclear retention, directly demonstrating defective HFE processing and trafficking (PMID:9162021). In a separate stable human neuroblastoma-cell system, C282Y altered HFE localization, ganglioside composition, sphingolipid-related gene expression, sphingosine-1-phosphate synthesis, morphology, and growth relative to wild-type HFE (PMID:21243428). A mouse model carrying the homologous C282Y substitution also showed abnormal HFE-dependent immune tolerance and cytotoxic T-cell responses (PMID:22531912). The concordant molecular, cellular, and in vivo findings support a damaging effect on the HFE gene product; the evidence is strong, although the studies were research assays rather than validated clinical diagnostic laboratory assays.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
PP3 is applicable because NM_000410.4:c.845G>A is a missense variant producing p.(Cys282Tyr); under the generic missense path, REVEL is the sole applicable predictor and SpliceAI is not used. REVEL is 0.872, which meets the supplied generic PP3 moderate threshold of >= 0.773, calibrated by Pejaver et al. 2022 (PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established.
Missense variant -> REVEL only. ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
Generic ACMG/AMP BA1 is met because NM_000410.4:c.845G>A (HFE p.Cys282Tyr) has an all-comers gnomAD v4.1 allele frequency of 0.0569823 (91,977/1,614,134 alleles), exceeding the published stand-alone threshold of >=0.05. The gnomAD v2.1 all-comers frequency is also 0.0337712 overall, with European non-Finnish frequency 0.057658; the available non-cancer subsets are concordant (v2.1 non-cancer exomes AF 0.0323788; v3.1 non-cancer genomes AF 0.0369491). No VCEP-specific population source restriction governs this case, so the generic all-comers default was used.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
No qualifying PS4 case-control comparison establishes that NM_000410.4:c.845G>A is significantly more prevalent in affected individuals than controls. Beutler et al. (PMID:11812557) screened 41,038 health-appraisal participants and found 152 homozygotes; the abstract states that common symptoms were no more prevalent among homozygotes than controls and that only one homozygote had signs suggesting hemochromatosis. This is not a case-versus-control variant-prevalence table, so an OR and 95% CI cannot be computed from the reported data. The literature_pass packet listed multiple papers under PS4, but its ai_classified_papers contained no paper classified as PS4; the reviewed exact-variant papers report clinical cases, cohort context, or functional findings without the required affected-versus-control variant counts.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... 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.
PM2 is not met because the variant is common in population controls rather than absent or extremely rare: gnomAD v4.1 all-comers AF=0.0569823 with 3,399 homozygotes, gnomAD v2.1 all-comers AF=0.0337712 with 276 homozygotes, and the non-cancer subsets also show AF=0.0323788 in v2.1 exomes and AF=0.0369491 in v3.1 genomes.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The exact variant has no ClinVar expert-panel submission: the ClinVar audit reports zero expert-panel submissions, while the available Pathogenic assertions are ordinary laboratory or single-submitter records. The reported pathogenic literature and aggregate ClinVar label therefore do not satisfy the restricted PP5 trigger.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is observed in many gnomAD homozygotes, including 3,399 in gnomAD v4.1 all-comers, 276 in gnomAD v2.1 all-comers, 223 in gnomAD v2.1 non-cancer exomes, and 143 in gnomAD v3.1 non-cancer genomes. However, these aggregate population records do not establish that the individuals were healthy adults with full penetrance expected at an early age, as required by BS2; therefore the observed homozygotes do not meet BS2.
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.
BS3 is not met. The available variant-specific functional studies do not show no damaging effect; instead, they show defective HFE beta-2-microglobulin interaction, loss of cell-surface expression, abnormal intracellular trafficking, and altered cellular and in vivo phenotypes for C282Y (PMID:9162021, PMID:21243428, PMID:22531912). Therefore the evidence is directionally opposite to the BS3 requirement, and no well-established benign functional assay result was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available allelic observations report C282Y in trans with G93R or S65C, not in cis. BP2 permits a trans observation only for a fully penetrant dominant gene/disorder, or a cis observation in any inheritance pattern. The available HFE-related hemochromatosis evidence describes a recessive context and provides no cis observation; therefore BP2 is not met.
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.
BP4 is applicable because NM_000410.4:c.845G>A is a missense variant, but the generic missense path permits REVEL only. REVEL is 0.872, which is above the highest supplied BP4 cutoff of <= 0.29 and therefore does not support a benign computational effect. The SpliceAI max delta of 0.075 is not considered for BP4 because splice prediction is not the applicable path for a missense variant; BayesDel is not usable because no generic ACMG-strength calibration is established.
Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The exact variant has no ClinVar expert-panel submission and no exact-variant expert-panel Benign or Likely benign classification. The flagged OMIM Benign record is not an expert-panel submission, and ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
PS2 cannot be assessed. The case materials do not document a disease-affected proband with this variant, absence of family history, or confirmed maternity and paternity. A ClinVar submission records origin as de novo, but it has no validated literature trail and is not sufficient to establish the required parental testing or clinical context. The governing definition requires both maternity and paternity confirmation; no such evidence is provided.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The variant is p.Cys282Tyr at residue 282. vcep_materials.json has no HFE domain_tables entry, and the reviewed literature documents functional importance of Cys282 but does not establish a qualifying mutational hotspot or critical, well-established functional domain together with absence of benign variation. Therefore PM1 cannot be assessed from the supplied evidence without re-deriving or independently validating domain and benign-variation data.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
HFE-related hemochromatosis is represented as a recessive disorder in the available case evidence. PMID:10575540 reports two affected probands with C282Y paired with another HFE variant: C282Y/G93R and C282Y/S65C. In Proband 2, RT-PCR, subcloning, and sequencing demonstrated that C282Y and G93R were on separate chromosomes, establishing trans phase; the paper likewise reports separate chromosomes for the C282Y/S65C observation. However, the available evidence does not independently establish G93R or S65C as pathogenic variants under the governing PM3 definition. Therefore, the phase and affected-proband observations are relevant but insufficient to assess PM3 as met.
For recessive disorders, detected in trans with a pathogenic variant...Note: This requires testing of parents (or offspring) to determine phase.
The variant is p.Cys282Tyr, but the supplied PM5 candidate file contains zero same-residue candidates and the reviewed paper extracts do not identify a different pathogenic missense substitution at Cys282. The required comparator evidence is therefore unavailable.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PM6 cannot be assessed. The materials do not provide a case-level report establishing that this variant arose de novo without parental confirmation. Although one ClinVar submission records origin as de novo, it has no validated literature trail and does not supply the proband phenotype, family history, or the parental testing information needed to distinguish an assumed de novo event from an unsupported database annotation.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed. No family pedigree or count of affected and unaffected relatives carrying or lacking NM_000410.4:c.845G>A is provided. PMID:10575540 reports family studies and molecular phasing in HFE probands with C282Y plus another HFE variant, including separation of C282Y from G93R or S65C, but this is phase information rather than cosegregation with disease in multiple affected family members. Therefore no PP1 evidence level can be assigned.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The reviewed evidence confirms that missense HFE variants occur in hemochromatosis, but it does not provide a gene-level assessment demonstrating both a low rate of benign missense variation and that missense variants are a common disease mechanism under a defined dataset or threshold. PP2 is therefore not assessed.
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 available case materials do not provide a patient phenotype or family history for this case that can be judged highly specific for hereditary hemochromatosis with a single genetic etiology. Variant reports in the literature cannot substitute for the phenotype of the present case.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The observed frequency is well above the generic BS1 default (gnomAD v4.1 all-comers AF 0.0569823; European non-Finnish AF 0.0710229; gnomAD v2.1 AF 0.0337712), but the default 1% threshold cannot be applied alone here. HFE p.Cys282Tyr is a common ancestry-enriched founder allele, and HFE-related hemochromatosis has age-dependent and reduced clinical penetrance; a maximum-credible-frequency calculation using disorder prevalence, penetrance, and allelic heterogeneity was not supplied. BS1 therefore remains not assessed rather than being assigned from the generic threshold alone.
Allele frequency is greater than expected for the disorder.
BS4 cannot be assessed. The materials contain no affected family members who were tested negative for NM_000410.4:c.845G>A and no pedigree-based non-segregation analysis. The absence of reported segregation data is not evidence of lack of segregation, so BS4 is not met and cannot be assigned without documented affected non-carriers and appropriate consideration of phenotype heterogeneity or phenocopies.
Lack of segregation in affected members of a family.
The variant is missense, satisfying BP1's variant-type premise, but the supplied evidence does not establish that HFE-related disease is caused primarily by truncating variants. The reviewed HFE disease reports instead document multiple missense variants, which is insufficient for a definitive gene-wide mechanism conclusion.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
No evidence in the case materials establishes that this variant was found in a case with an alternate molecular basis for disease. The presence of other HFE variants in some published cases is not evidence for an alternate molecular basis in this case.
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.845G>A in HFE is a missense substitution predicted to produce NP_000401.1:p.(Cys282Tyr). 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.845G>A in HFE is a missense substitution predicted to produce NP_000401.1:p.(Cys282Tyr). 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
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.845G>A in HFE is a missense substitution predicted to produce NP_000401.1:p.(Cys282Tyr). 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.845G>A in HFE is a missense substitution predicted to produce NP_000401.1:p.(Cys282Tyr). 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)83807 / 1,180,000 | 0.0713173 hom |
| Remaining individuals3507 / 62,506 | 0.056155 hom |
| Amish41 / 912 | 0.0453 hom |
| European (Finnish)2357 / 64,038 | 0.03744 hom |
| Admixed American904 / 60,020 | 0.01511 hom |
| Ashkenazi Jewish356 / 29,606 | 0.0126 hom |
| African/African American790 / 75,038 | 0.0116 hom |
| South Asian196 / 91,088 | 0.00221 hom |
| Middle Eastern10 / 6,048 | 0.0017 |
| East Asian9 / 44,878 | 0.0002 |
| European (non-Finnish)7435 / 128,950 | 0.058243 hom |
| Remaining individuals281 / 7,224 | 0.0398 hom |
| European (Finnish)879 / 25,108 | 0.03517 hom |
| Admixed American494 / 35,430 | 0.0145 hom |
| Ashkenazi Jewish124 / 10,366 | 0.0122 hom |
| African/African American260 / 24,962 | 0.011 hom |
| South Asian68 / 30,616 | 0.0022 |
| East Asian3 / 19,952 | 0.00015 |
This variant is present in gnomAD v4.1 (AF= 0.0569823; MAF= 5.69823%, 91977/1614134 alleles, homozygotes = 3399) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0710229; MAF= 7.10229%, 83807/1180000 alleles, homozygotes = 3173); grpmax FAF= 0.0706191.
This variant is present in gnomAD v2.1 (AF= 0.0337712; MAF= 3.37712%, 9544/282608 alleles, homozygotes = 276) and has highest observed frequency in the European (non-Finnish) population (AF= 0.057658; MAF= 5.76580%, 7435/128950 alleles, homozygotes = 243); grpmax FAF= 0.056289.
This variant is present in gnomAD-Canada v1.0 (AF= 0.03758010209623113, 692/18414 alleles, homozygotes = 14).
PP3 is applicable because NM_000410.4:c.845G>A is a missense variant producing p.(Cys282Tyr); under the generic missense path, REVEL is the sole applicable predictor and SpliceAI is not used. REVEL is 0.872, which meets the supplied generic PP3 moderate threshold of >= 0.773, calibrated by Pejaver et al. 2022 (PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established.
Missense variant -> REVEL only. ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP4 is applicable because NM_000410.4:c.845G>A is a missense variant, but the generic missense path permits REVEL only. REVEL is 0.872, which is above the highest supplied BP4 cutoff of <= 0.29 and therefore does not support a benign computational effect. The SpliceAI max delta of 0.075 is not considered for BP4 because splice prediction is not the applicable path for a missense variant; BayesDel is not usable because no generic ACMG-strength calibration is established.
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.845G>A in HFE is a missense substitution predicted to produce NP_000401.1:p.(Cys282Tyr). 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 = 0.07). REVEL score = 0.872. BayesDel score = 0.517213.
10 paper records listed. 6 cited in the classification.
In Proband 2 (HFE genotype C282Y/G93R), RT-PCR, with subsequent subcloning and sequencing, revealed that his HFE mutations occurred on separate chromosomes.
Location Results, Association of Uncommon HFE Coding Region Mutations to C282Y and H63D; Table 2
Context Twenty Alabama hemochromatosis probands with atypical HFE genotypes underwent HFE exon sequencing; C282Y phase was assessed by family studies and RT-PCR followed by subcloning and sequencing.
Cells expressing the C282Y variant showed significant (>2-fold) increases in transcription of five genes and decreases in two compared to that seen for cells expressing WT-HFE.
Location Abstract; Results, paragraphs describing lipid-raft association, ganglioside composition, and gene expression; Table 1; Figures 2–7
Context In vitro study using SH-SY5Y human neuroblastoma cells stably transfected to express FLAG-tagged wild-type HFE, C282Y-HFE, or H63D-HFE; lipid-raft fractionation, ganglioside HPTLC, cholera toxin B binding, RT-qPCR of 14 genes, Western blotting, and sphingosine-1-phosphate synthesis assays.
These mHfe-C282→Y mutated mice positively selected TCR-transgenic CD8+ T cells as efficiently as DBA/2 mHfe KO mice and these cells differentiated in mHFE-specific CTL when stimulated by mHFE+ cells in vitro.
Location Results, “C282→Y mHFE-expressing TCR-transgenic mHFE KO and WT mice T cell analysis,” p. 853; skin-graft results and discussion, pp. 855 and 858
Context Mouse knock-in model: C57BL/6 mHfe C282→Y mice crossed into DBA/2 Rag2-knockout mice carrying an anti-mHFE TCR transgene; flow-cytometric T-cell analysis, in-vitro cytotoxicity assays, and DBA/2 skin-graft experiments.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Location Proposed Criteria for Interpretation of Sequence Variants, introductory paragraph
Context ACMG/AMP/CAP workgroup consensus and review of variant-classification guidance; no HFE-specific cohort or assay.
In Caucasians, more than 80% of hemochromatosis cases are related to homozygosity for the p.Cys282Tyr (c.845G > A) HFE variant.
Location Introduction; Results, paragraphs 1–3; Table I; Table II
Context Prospective cohort of 206 patients referred for suspected type 1 hemochromatosis from 2004 to 2010; sequencing of HFE and other hemochromatosis genes with family studies when possible.
The C282Y mutation completely abrogates this interaction and disrupts intracellular protein trafficking.
Location Abstract; Results and Discussion, Figures 1–3
Context Stable human embryonic kidney 293 cell lines expressing wild-type, C282Y-mutant, or H63D-mutant HLA-H; co-immunoprecipitation, Western blotting, immunofluorescence, and subcellular fractionation.
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= 0.0569823; MAF= 5.69823%, 91977/1614134 alleles, homozygotes = 3399) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0710229; MAF= 7.10229%, 83807/1180000 alleles, homozygotes = 3173); grpmax FAF= 0.0706191.
This variant is present in gnomAD v2.1 (AF= 0.0337712; MAF= 3.37712%, 9544/282608 alleles, homozygotes = 276) and has highest observed frequency in the European (non-Finnish) population (AF= 0.057658; MAF= 5.76580%, 7435/128950 alleles, homozygotes = 243); grpmax FAF= 0.056289.
This variant is present in gnomAD-Canada v1.0 (AF= 0.03758010209623113, 692/18414 alleles, homozygotes = 14).
This variant has been reported in ClinVar as Pathogenic (43 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as risk factor (1 clinical laboratory) and as other (1 clinical laboratory) and as Pathogenic, low penetrance (1 clinical laboratory) and as pathogenic (1 clinical laboratory). (ClinVarID = 9)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.872. BayesDel score = 0.517213.
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; COSV107360943, n = 1 times).
This variant does not lie in a statistically significant hotspot.