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rs1799945

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 6P and 6B. PM1PP5_StrongBP4BS1_SupportingBS2

The NM_000410.4(HFE):c.187C>G(p.His63Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,613,898 control chromosomes in the GnomAD database, including 15,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other,other (★★). Synonymous variant affecting the same amino acid position (i.e. H63H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.10 ( 1005 hom., cov: 31)
Exomes 𝑓: 0.14 ( 14272 hom. )

Consequence

HFE
NM_000410.4 missense

Scores

7
9

Clinical Significance

Pathogenic/Likely pathogenic/Pathogenic, low penetrance; other criteria provided, multiple submitters, no conflicts P:40U:2B:1O:6

Conservation

PhyloP100: 1.87
Variant links:
Genes affected
HFE (HGNC:4886): (homeostatic iron regulator) The protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). It is thought that this protein functions to regulate iron absorption by regulating the interaction of the transferrin receptor with transferrin. The iron storage disorder, hereditary haemochromatosis, is a recessive genetic disorder that results from defects in this gene. [provided by RefSeq, May 2022]
H2BC4 (HGNC:4757): (H2B clustered histone 4) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. The protein has antibacterial and antifungal antimicrobial activity. The main transcript variant of this gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. This transcript variant lacks a polyA tail but instead contains a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Apr 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1
In a region_of_interest Alpha-1 (size 91) in uniprot entity HFE_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_000410.4
PP5
Variant 6-26090951-C-G is Pathogenic according to our data. Variant chr6-26090951-C-G is described in ClinVar as [other, other]. Clinvar id is 10.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=31, Benign=1, Pathogenic_low_penetrance=1, Likely_pathogenic=1, Uncertain_significance=2, not_provided=4, other=1}. Variant chr6-26090951-C-G is described in Lovd as [Likely_pathogenic]. Variant chr6-26090951-C-G is described in Lovd as [Pathogenic]. Variant chr6-26090951-C-G is described in Lovd as [Likely_benign].
BP4
Computational evidence support a benign effect (MetaRNN=0.0015847087).. Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.102 (15444/152144) while in subpopulation NFE AF= 0.15 (10219/67976). AF 95% confidence interval is 0.148. There are 1005 homozygotes in gnomad4. There are 7371 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd at 1005 AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HFENM_000410.4 linkuse as main transcriptc.187C>G p.His63Asp missense_variant 2/6 ENST00000357618.10
HFE-AS1NR_144383.1 linkuse as main transcriptn.84G>C non_coding_transcript_exon_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HFEENST00000357618.10 linkuse as main transcriptc.187C>G p.His63Asp missense_variant 2/61 NM_000410.4 P3Q30201-1

Frequencies

GnomAD3 genomes
AF:
0.102
AC:
15453
AN:
152026
Hom.:
1005
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0296
Gnomad AMI
AF:
0.0724
Gnomad AMR
AF:
0.110
Gnomad ASJ
AF:
0.121
Gnomad EAS
AF:
0.0272
Gnomad SAS
AF:
0.0777
Gnomad FIN
AF:
0.0959
Gnomad MID
AF:
0.108
Gnomad NFE
AF:
0.150
Gnomad OTH
AF:
0.131
GnomAD3 exomes
AF:
0.109
AC:
27472
AN:
251484
Hom.:
1832
AF XY:
0.112
AC XY:
15193
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0274
Gnomad AMR exome
AF:
0.100
Gnomad ASJ exome
AF:
0.107
Gnomad EAS exome
AF:
0.0347
Gnomad SAS exome
AF:
0.0803
Gnomad FIN exome
AF:
0.104
Gnomad NFE exome
AF:
0.144
Gnomad OTH exome
AF:
0.120
GnomAD4 exome
AF:
0.135
AC:
197513
AN:
1461754
Hom.:
14272
Cov.:
34
AF XY:
0.134
AC XY:
97535
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.0276
Gnomad4 AMR exome
AF:
0.103
Gnomad4 ASJ exome
AF:
0.116
Gnomad4 EAS exome
AF:
0.0312
Gnomad4 SAS exome
AF:
0.0795
Gnomad4 FIN exome
AF:
0.106
Gnomad4 NFE exome
AF:
0.150
Gnomad4 OTH exome
AF:
0.125
GnomAD4 genome
AF:
0.102
AC:
15444
AN:
152144
Hom.:
1005
Cov.:
31
AF XY:
0.0991
AC XY:
7371
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0296
Gnomad4 AMR
AF:
0.110
Gnomad4 ASJ
AF:
0.121
Gnomad4 EAS
AF:
0.0269
Gnomad4 SAS
AF:
0.0773
Gnomad4 FIN
AF:
0.0959
Gnomad4 NFE
AF:
0.150
Gnomad4 OTH
AF:
0.130
Alfa
AF:
0.136
Hom.:
1184
Bravo
AF:
0.100
TwinsUK
AF:
0.143
AC:
530
ALSPAC
AF:
0.136
AC:
526
ESP6500AA
AF:
0.0315
AC:
139
ESP6500EA
AF:
0.151
AC:
1301
ExAC
AF:
0.107
AC:
12942
Asia WGS
AF:
0.0630
AC:
218
AN:
3478
EpiCase
AF:
0.148
EpiControl
AF:
0.146

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance; other
Submissions summary: Pathogenic:40Uncertain:2Benign:1Other:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hemochromatosis type 1 Pathogenic:24Uncertain:1Other:2
Likely pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 26, 2024- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Immunology and Genetics KaiserslauternMar 09, 2024ACMG Criteria: PS1, PS3, PP5; Variant was found in heterozygous state -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterMay 15, 2023- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaSep 25, 2018This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PS4,PP4. -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJan 05, 2022PS3, PM3_Strong -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinDec 21, 2021ACMG classification criteria: PS3, PS4, PM3 -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenDec 27, 2022- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease CompanyAug 26, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Medicine Lab, University of California San FranciscoJul 21, 2020- -
not provided, no classification providedliterature onlyOMIMMar 12, 2024- -
Uncertain significance, flagged submissionclinical testingFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsDec 25, 2021A heterozygous missense variation in exon 2 of the HFE gene that results in the amino acid substitution of Aspartic Acid for Histidine at codon 63 was detected. The observed variant c.187C>G (p.His63Asp) has previously been reported in a patient affected with Hemochromatosis and functional studies have shown that H63D disrupts normal protein function. The variant has a minor allele frequency of 7% and 10% in the 1000 genomes and gnomAD databases respectively. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
Pathogenic, criteria provided, single submitterclinical testingGenomic Medicine Lab, University of California San FranciscoMar 28, 2023- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityJan 27, 2016The c.187C>G (p.His63Asp) missense variant is widely recognized as one of the two most common disease-causing variants in the HFE gene. Compound heterozygotes for p.Cys282Tyr and p.His63Asp are common in the Caucasian population, and together with homozygotes for the p.Cys282Tyr, account for 87% of individuals of European origin with HFE-HH. However, it is important to note that only ~ 0.5%-2.0% of compound heterozygous individuals develop clinical evidence of the disease due to incomplete penetrance (GeneReviews: Seckington et al., 2015; Ramrakhiani and Bacon, 1998; Morrison et al., 2003). In summary, this variant c.187C>G, (p.His63Asp) meets our criteria for Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaDec 16, 2021- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 18, 2023The HFE c.187C>G (p.His63Asp) missense variant is well described in the literature as a pathogenic variant with significantly reduced penetrance for HFE hemochromatosis. Approximately 1% of individuals of European ancestry with HFE hemochromatosis are homozygous for the p.His63Asp variant, and between 3-8% are compound heterozygous for the p.His63Asp variant and the well-known p.Cys282Tyr pathogenic variant (PMID: 20301613; PMID: 8696333). Although biochemical abnormalities may be present, only two percent or fewer of individuals who are compound heterozygous for the p.His63Asp variant are expected to develop clinical symptoms of iron overload and HFE hemochromatosis (PMID: 11874997; 19554541; 26365338). Heterozygosity for the p.His63Asp variant ranges from 8.5% in the Asian population to 25% in northern Europeans (PMID: 20301613), with the variant being reported at a frequency of 0.150400 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.2), where it is also found in a total of 1005 homozygotes. This allele frequency is high but is consistent with estimates of disease prevalence, reduced penetrance, and a mild phenotype. The p.His63Asp variant is predicted to disrupt a pH-dependent intramolecular salt bridge in the alpha-2 domain, thereby affecting interaction of the protein with the transferrin receptor (PMID: 20301613). Based on the available evidence, the c.187C>G (p.His63Asp) variant is classified as pathogenic for hemochromatosis but with significantly reduced penetrance. -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 06, 2021Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with haemochromatosis (MIM#235200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. The variant has also been shown to have variable phenotypic expression and reduced penetrance (GeneReviews, PMID: 19554541). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0307 - Variant is present in gnomAD (v2) at a frequency >5% (26,546 heterozygotes, 2,023 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated class I histocompatibility antigen, domains alpha 1 and 2 (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The is one of the most common, low penetrance variants that has previously been described as pathogenic in multiple patients with haemochromatosis (ClinVar; PMID: 26153218); either in a homozygous state or in trans with p.(Cys282Tyr). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitterclinical testingClinical Genomics Program, Stanford MedicineMay 13, 2021• The p.His63Asp variant in the HFE gene has been identified in the homozygous state in approximately 1% of individuals of European ancestry with HFE hemochromatosis, and in the compound heterozygous state with p.Cys282Tyr in approximately 3-8% of individuals of European ancestry with HFE hemochromatosis (Barton and Edwards, 2018). • The p.His63Asp variant is described as a low-penetrant allele and is rarely associated with clinical disease in the homozygous or compound heterozygous state (Gochee et al., 2002; Gurrin et al., 2009). • Individuals heterozygous for the p.His63Asp variant may demonstrate evidence of biochemical disease, including mildly elevated serum transferrin-iron saturation and serum ferritin concentration, but do not develop clinical manifestations of disease (Allen et al., 2008; Pedersen and Milman, 2009). • This variant has been identified in 18,635/129,168 European (non-Finnish) chromosomes (30,592/282,844 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although the p.His63Asp variant is seen at a frequency greater than 5% in the general population, this variant is recognized as a common low-penetrant variant that is an exception to ACMG/AMP classification guidelines (Ghosh et al., 2018). • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.His63Asp variant as pathogenic for autosomal recessive HFE hemochromatosis based on the information above. [ACMG evidence codes used: PS4] -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsNov 26, 2015- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 26, 2021Variant summary: HFE c.187C>G (p.His63Asp) results in a non-conservative amino acid change located in the MHC class I-like antigen recognition-like domain (IPR011161) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.11 in 251484 control chromosomes in the gnomAD database, including 1832 homozygotes. c.187C>G has been reported as a common disease variant in the literature in individuals affected with Hemochromatosis Type 1, in both homozygous and compound heterozygous states, but most frequently in trans with the most common disease variant c.845G>A (p.Cys282Tyr) (e.g. Feder_1996, Kelley_2014). These data indicate that the variant is likely to be associated with disease, however the variant appears to have very low penetrance, as the majority of homozygous or compound heterozygous individuals with this variant do not exhibit clinical symptoms of hemochromatosis despite some cases having elevated serum ferritin and transferrin saturation levels (e.g. Beutler_2002, Pedersen_2009). Several publications report experimental evidence evaluating an impact on protein function. While p.His63Asp was shown to have normal levels of association with beta2-globulin and expression of HFE on the cell surface in contrast to impairment observed in cells with the other common pathogenic variant p.Cys282Tyr (e.g. Waheed_1997), p.His63Asp was shown to induce ER-stress in-vitro and in a transgenic mouse model (e.g. Liu_2011). Transgenic mice expressing the murine equivalent of this variant were also reported to have increased iron storage and decreased levels of iron mobilization at 12 months of age (e.g. Nandar_2013). The variant has also been reported to alter the expression levels of several genes involved in sphingolipid metabolism (e.g. Ali-Rahmani_2011) and to affect cellular glutamate levels (e.g. Mitchell_2011). Sixteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Thirteen of these submitters report the variant as either Pathogenic or a risk factor for disease. Based on the evidence outlined above, the variant was classified as pathogenic with very low penetrance in association with Hemochromatosis. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsNov 25, 2023- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 26, 2019NM_000410.3(HFE):c.187C>G(H63D) is classified as pathogenic in the context of HFE-associated hereditary hemochromatosis. H63D is only associated with clinical hemochromatosis in the presence of some other genetic variant or condition that affects iron metabolism such as the C282Y variant or liver disease. Sources cited for classification include the following: PMID 9462220, 11904676, 11358905, 19159930, 19554541 and 14673107. Classification of NM_000410.3(HFE):c.187C>G(H63D) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasOct 09, 2023- -
Pathogenic, criteria provided, single submitterresearchUNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill-The HFE c.187C>G (p.H63D) variant is a pathogenic variant seen in 10.8% of the human population in gnomAD. Indviduals with the p.H63D variant are considered carriers of hemochromatosis, although this variant is associated with less severe iron overload and reduced penetrance compared to another pathogenic HFE variant, c.845G>A, p.C282Y (PMID: 19159930; 20301613). -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 14, 2015- -
Pathogenic, no assertion criteria providedresearchGenomics And Bioinformatics Analysis Resource, Columbia University-- -
not provided Pathogenic:11Other:1
other, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 26, 2018- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 08, 2020Published functional studies demonstrate a damaging effect (Nandar et al., 2013; Mitchell et al., 2011); This variant is associated with the following publications: (PMID: 19401444, 20031541, 8696333, 11399207, 31028937, 19159930, 19271219, 24920245, 23389292, 24729993, 20478760, 20640879, 17042772, 25262004, 21925577, 23178241, 19291797, 18525129, 21349849, 19820015, 20097100, 18846434, 23222517, 21514009, 19560233, 24439478, 21243428, 22232660, 20560808, 17450498, 19115475, 11874997, 19554541, 25117103, 26501199, 21909115, 27661980, 26365338, 27153395, 11903355, 17339196, 25687342, 26497867, 28110185, 19214108, 30291871, 11358905, 9356458, 9341868, 20301613, 25767899, 19176287, 18566337, 16132052, 15858186, 15347835, 14729817, 12429850, 11532995, 11479183, 11423500, 31016714, 31180159, 31640930, 23792061, 32014855, 29301508, 31980526, 34426522, 11189980, 11336458, 11478530, 11531973, 9382962, 32641076, 10792295, 10090890, 32874917, 32746448, 23429074) -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsMar 25, 2022- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenSep 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024HFE: PM3:Strong, PM1, PP4:Moderate, PS3:Moderate, PM2:Supporting -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The HFE p.His63Asp variant is associated with Hereditary Hemochromatosis (HH), an autosomal-recessive disorder caused by pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp (Gurrin_2009_PMID: 19554541). This variant was identified in dbSNP (ID: rs1799945), LOVD 3.0 (classified as pathogenic) and ClinVar (classified as pathogenic for hemochromatosis by Invitae, GeneDx, Illumina, Blueprint Genetics, Counsyl, University of Chicago, Partners Laboratory for Molecular Medicine and Knight Diagnostic Laboratories,Oregon Health and Sciences University). The variant was identified in control databases in 30592 of 282844 chromosomes (2023 homozygous) at a frequency of 0.108159 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 18635 of 129168 chromosomes (freq: 0.1443), Other in 872 of 7222 chromosomes (freq: 0.1207), Ashkenazi Jewish in 1113 of 10370 chromosomes (freq: 0.1073), European (Finnish) in 2598 of 25118 chromosomes (freq: 0.1034), Latino in 3556 of 35438 chromosomes (freq: 0.1003), South Asian in 2457 of 30616 chromosomes (freq: 0.08025), East Asian in 680 of 19952 chromosomes (freq: 0.03408) and African in 681 of 24960 chromosomes (freq: 0.02728). Functional studies show that the HFE p.H63D variant impacts brain iron homeostasis (Nandar_2013_PMID: 23429074). Other studies indicate that the presence of the p.H63D variant results in a significant increase in serum transferrin saturation but does not result in significant iron overload and in the absence of the p.C282Y variant, the p.H63D variant is not clinically significant (Goochee_2002_PMID: 11874997). The homozygous state is considered to be extremely low penetrance and associated with variable phenotypes (Kelley_2014_PMID: 24729993). The c.187C>G variant occurs outside of the splicing consensus sequence and the in silico splicing prediction software programs do not predict any difference in splicing (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer). The p.His63 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. References: Gurrin, Lyle C., et al. “HFE C282Y/H63D Compound Heterozygotes Are at Low Risk of Hemochromatosis-Related Morbidity.” Hepatology, vol. 50, no. 1, July 2009, pp. 94–101. Nandar, Wint, et al. “A Mutation in the HFE Gene Is Associated with Altered Brain Iron Profiles and Increased Oxidative Stress in Mice.” Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1832, no. 6, 2013, pp. 729–741. Gochee, Peter A., et al. “A Population-Based Study of the Biochemical and Clinical Expression of the H63D Hemochromatosis Mutation.” Gastroenterology, vol. 122, no. 3, 2002, pp. 646–651. Kelley, Melissa, et al. “Iron Overload Is Rare in Patients Homozygous for the H63D Mutation.” Canadian Journal of Gastroenterology and Hepatology, vol. 28, no. 4, 2014, pp. 198–202. -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJan 25, 2022- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Hereditary hemochromatosis Pathogenic:1Other:1
Pathogenic, low penetrance, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 63 of the HFE protein (p.His63Asp). This variant is present in population databases (rs1799945, gnomAD 14%), and has an allele count higher than expected for a pathogenic variant. This is a very common, low penetrance variant that is known to contribute to hemochromatosis when present with a second pathogenic allele in HFE. An estimated 1.5% of individuals of European descent who are affected with hemochromatosis are homozygous for this variant (PMID: 11479183), however, penetrance of the homozygous genotype is very low and is associated with variable phenotypes (PMID: 24729993, 11399207, 16132052, 11358905). ClinVar contains an entry for this variant (Variation ID: 10). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HFE protein function. Experimental studies have shown that this missense change affects HFE function (PMID: 9162021, 9356458, 12429850, 14673107). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the HFE gene, it has been classified as Pathogenic (low penetrance). -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 11-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
not specified Uncertain:1Benign:1
Uncertain significance, flagged submissionclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 05, 2020proposed classification - variant undergoing re-assessment, contact laboratory -
Benign, flagged submissionclinical testingPathology and Clinical Laboratory Medicine, King Fahad Medical City-- -
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Region OstergotlandMar 25, 2021PM3, PP1, PP5, PS4 -
Variegate porphyria Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyJan 13, 2020Contributing pathogenic variant when co-inherited with other pathogenic variants in HFE or PPOX genes, but not pathogenic alone, even in the homozygous state. -
Alzheimer disease;C0162532:Variegate porphyria;C0268323:Familial porphyria cutanea tarda;C2673520:Microvascular complications of diabetes, susceptibility to, 7;C3280096:Transferrin serum level quantitative trait locus 2;C3469186:Hemochromatosis type 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Abnormality of iron homeostasis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University Hospital MuensterDec 10, 2021ACMG categories: PS1,PS3,PS4,PP4 -
Cystic fibrosis Other:1
risk factor, no assertion criteria providedresearchCenter for Computational Genomics and Data Science, University of AlabamaApr 01, 2019- -
Bronze diabetes Other:1
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant identified in multiple participants and classified as Pathogenic. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Uncertain
-0.070
Cadd
Benign
21
Dann
Uncertain
0.99
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.079
N
LIST_S2
Benign
0.56
T;T;T;T;T;T;T
MetaRNN
Benign
0.0016
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.10
D
MutationTaster
Benign
1.0
P;P;P;P;P;P;P;P;P;P;P
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.2
N;N;N;N;N;N;N
REVEL
Uncertain
0.32
Sift
Uncertain
0.016
D;T;D;T;D;D;D
Sift4G
Benign
0.15
T;T;T;T;T;T;T
Polyphen
0.15
B;D;B;B;D;B;.
Vest4
0.30
MPC
0.99
ClinPred
0.012
T
GERP RS
3.5
Varity_R
0.45
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1799945; hg19: chr6-26091179; COSMIC: COSV58513169; COSMIC: COSV58513169; API