rs1799945
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS1_Supporting
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 Pathogenic low penetrance,other (★★).
Frequency
Consequence
NM_000410.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.102 AC: 15453AN: 152026Hom.: 1005 Cov.: 31
GnomAD3 exomes AF: 0.109 AC: 27472AN: 251484Hom.: 1832 AF XY: 0.112 AC XY: 15193AN XY: 135916
GnomAD4 exome AF: 0.135 AC: 197513AN: 1461754Hom.: 14272 Cov.: 34 AF XY: 0.134 AC XY: 97535AN XY: 727184
GnomAD4 genome 0.102 AC: 15444AN: 152144Hom.: 1005 Cov.: 31 AF XY: 0.0991 AC XY: 7371AN XY: 74366
ClinVar
Submissions by phenotype
Hemochromatosis type 1 Pathogenic:27Uncertain:1Other:2
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PS3+PM3_VeryStrong -
ACMG classification criteria: PS3, PS4, PM3 -
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The 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. -
NM_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. -
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PS4,PP4. -
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PS3, PM3_Strong -
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). -
ACMG Criteria: PS1, PS3, PP5; Variant was found in heterozygous state -
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A 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. -
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Variant 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. -
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Based 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 -
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• 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] -
The 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. -
The observed missense c.187C>G(p.His63Asp) variant in HFE gene has been reported previously in homozygous or compound heterozygous state in multiple individuals affected with hemochromatosis (Atkins et al., 2022), however, penetrance of the homozygous genotype is very low and is associated with variable phenotypes. Experimental studies have shown that this missense change affects HFE function (Tomatsu et al., 2003). This variant has been reported with the high allele frequency of 10.9% in the gnomAD Exomes. This variant has been submitted to the ClinVar database with Benign / Uncertain Significance / Risk factor / Pathogenic (multiple submitters). The amino acid His at position 63 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.His63Asp in HFE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.Though the variant frequency is very high in the population, the variant is enriched in patints with HFE hemochromatosis as compared to the general population (Burke et al., 2000). For these reasons, this variant has been classified as a Pathogenic variant which acts as a risk factor for the development of the disease. -
not provided Pathogenic:12Other:1
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Published 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) -
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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. -
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- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
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HFE: PM3:Strong, PM1, PP4:Moderate, PS3:Moderate, PM2:Supporting -
Hereditary hemochromatosis Pathogenic:1Other:1
This 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). Invitae Evidence 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 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). -
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
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proposed classification - variant undergoing re-assessment, contact laboratory -
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
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Cardiomyopathy Pathogenic:1
PM3, PP1, PP5, PS4 -
Variegate porphyria Pathogenic:1
Contributing pathogenic variant when co-inherited with other pathogenic variants in HFE or PPOX genes, but not pathogenic alone, even in the homozygous state. -
See cases Pathogenic:1
ACMG categories: PS1,PS3,PS4,PP4 -
Cystic fibrosis Other:1
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Bronze diabetes Other:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at