rs1800562
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 9P and 2B. PP3PP5_Very_StrongBP4BS1_Supporting
The NM_000410.4(HFE):c.845G>A(p.Cys282Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.057 in 1,614,134 control chromosomes in the GnomAD database, including 3,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic low penetrance,other,risk factor (★★).
Frequency
Consequence
NM_000410.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0373 AC: 5679AN: 152164Hom.: 151 Cov.: 31
GnomAD3 exomes AF: 0.0332 AC: 8344AN: 251236Hom.: 244 AF XY: 0.0323 AC XY: 4391AN XY: 135842
GnomAD4 exome AF: 0.0590 AC: 86298AN: 1461852Hom.: 3248 Cov.: 34 AF XY: 0.0568 AC XY: 41284AN XY: 727228
GnomAD4 genome 0.0373 AC: 5679AN: 152282Hom.: 151 Cov.: 31 AF XY: 0.0341 AC XY: 2539AN XY: 74446
ClinVar
Submissions by phenotype
Hemochromatosis type 1 Pathogenic:28Benign:1Other:1
Variant summary: HFE c.845G>A (p.Cys282Tyr) results in a non-conservative amino acid change located in the Immunoglobulin C1-set domain (IPR003597) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.033 in 251236 control chromosomes in the gnomAD database, including 244 homozygotes. c.845G>A has been reported in the literature as the most common mutation found in individuals with Hemochromatosis Type 1, being identified as homozygous or compound heterozygous with another pathogenic variant in approximately 80-90% of reported cases, most frequently in individuals of European ancestry (e.g. Feder_1996, LeGac_2004, Beutler_2002, Yonal_2007, vanGemmeren_2015, deTayrac_2015, Zhang_2020). These data indicate that the variant is likely to be associated with disease, however the variant appears to have significantly reduced penetrance, as the majority of homozygous or compound heterozygous individuals with this variant do not exhibit clinical symptoms of the disorder despite some cases having elevated serum ferritin and transferrin saturation levels (e.g. Feder_1996, Beutler_2002, Yonal_2007). The mechanisms behind the variable expressivity of this variant are not known, but it has been proposed that other genetic variants could modify the phenotype exhibited by individuals who are homozygous for this variant (e.g. LeGac_2004, deTayrac_2015). In-vitro experimental evidence suggests that the Cys282Tyr-mutant protein has impaired intracellular trafficking and accelerated degradation compared to wild-type HFE (e.g. Waheed_1997) and that cells expressing the variant have altered expression of genes involved in sphingolipid metabolism (e.g. Ali-Rahmani_2011). In addition, an in-vivo study reported a loss of CD8+ T-cell tolerance to HFE in transgenic mice expressing the C282Y variant (e.g. Boucherma_2012) . Seventeen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Sixteen of these laboratories cited the variant as pathogenic/likely pathogenic or as a risk factor for disease. Based on the evidence outlined above, the variant was classified as pathogenic with low penetrance for developing Hemochromatosis. -
The c.845G>A (p.Cys282Tyr) variant in the HFE gene in the homozygous state has been reported as a common cause of hereditary hemochromatosis with high penetrance of biochemically defined iron overload but low penetrance of clinically defined iron overload [OMIM:613609.0001; PMID 8896549, 10381492, 18199861]. This variant has been detected at high frequency in the ExAC population database (up to 5% in Europeans) (http://exac.broadinstitute.org/variant/6-26093141-G-A). Cysteine at amino acid position 282 of the HFE protein is highly conserved in mammals and computer-based algorithms predict this p.Cys282Tyr change to be deleterious. This variant is classified as pathogenic.<BR>Apparent homozygosity of this variant may be caused by the presence of the mutant allele on both alleles of this individual, or the presence of a mutant allele on one allele and an exonic deletion on the opposite allele. Copy number variant (CNV) analysis or segregation analysis is necessary to assess the apparent homozygosity status of this variant. -
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• The p.Cys282Tyr variant in the HFE gene has been identified in the homozygous state in approximately 60- 90% of individuals of European ancestry with HFE hemochromatosis, and in the compound heterozygous state with p.His63Asp in approximately 3-8% of individuals of European ancestry with HFE hemochromatosis (Barton and Edwards, 2018). • The p.Cys282Tyr variant is associated with a high penetrance for biochemical evidence of iron overload, but with a low penetrance for clinical manifestations of iron overload with studies reporting evidence of clinical disease present in as low as 2% and as high as 33% of p.Cys282Tyr homozygotes (Beutler et al., 2002; Whitlock et al., 2006). • Individuals heterozygous for the p.Cys282Tyr 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 7,435/128,950 European (non-Finnish) chromosomes (9,544/282,608 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although the p.Cys282Tyr 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.Cys282Tyr variant as pathogenic for autosomal recessive HFE hemochromatosis based on the information above. [ACMG evidence codes used: PS4; PP3] -
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The HFE c.845G>A (p.Cys282Tyr) variant has been reported in the homozygous or compound heterozygous state in many individuals affected with hereditary hemochromatosis and is considered the most common cause of hereditary hemochromatosis (Barton JC and Edwards CQ, PMID: 20301613). Studies show penetrance rates of severe iron overload to be as high as 35% and severe liver disease in 9–24% among male p.Cys282Tyr homozygotes (Grosse SD et al., PMID: 28771247). This variant has been reported in the ClinVar database as a germline pathogenic variant by many submitters. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HFE function. In support of these predictions, a homozygous mouse model showed postnatal iron loading and in vitro functional studies have shown that the variant causes reduced function (Ali-Rahmani F et al., PMID: 21243428; Boucherma R et al., PMID: 22531912; Levy JE et al., PMID: 10381492). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic with reduced penetrance. -
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NM_000410.3(HFE):c.845G>A(C282Y) is classified as pathogenic in the context of HFE-associated hereditary hemochromatosis. Please note that clinical symptoms are uncommon in C282Y homozygotes. Sources cited for classification include the following: PMID 9162021, 9356458, 8931958, 9341868, 9462220 and 11812557. Classification of NM_000410.3(HFE):c.845G>A(C282Y) 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. -
ACMG Criteria: PS3, PS4, PM3, PP1_M, PP5; Variant was found in compound heterozygous state with NM_000410.4:c.187C>G. -
The HFE c.845G>A (p.Cys282Tyr) missense variant results in the substitution of cysteine at amino acid position 282 to tyrosine. This variant is one of the two most common and well-studied pathogenic variants associated with HFE hemochromatosis. Approximately 60-90% of individuals of European ancestry with HFE hemochromatosis are homozygous for the variant and between 3-8% of individuals are compound heterozygous (Feder et al. 1996; Morrison et al. 2003; Gallego et al. 2015; Press et al. 2016; Barton and Edwards 2018). Disease penetrance for c.845G>A variant carriers is variable (Beutler et al. 2002; Pedersen et al. 2009; Gurrin et al. 2009), with homozygotes being at a greater risk for iron overload than compound heterozygotes (Gallego et al. 2015; Barton and Edwards 2018). The c.845G>A variant affects HFE protein activity by preventing the formation of a disulfide bridge in the alpha-3 domain, which impairs the beta-2-microglobulin interaction and prevents the protein from reaching the cell surface (Feder et al. 1997; Barton and Edwards 2018). The c.845G>A variant has a frequency of 5-7% in Caucasians (Press et al. 2016) and is reported at a frequency of 0.064660 in the European (non-Finnish) population (including 137 homozygotes) of the Genome Aggregation Database (version 3.1.2). This allele frequency is high but is consistent with estimates of disease prevalence. Based on the available evidence, the c.845G>A (p.Cys282Tyr) variant is classified as pathogenic for HFE hemochromatosis but is noted to have reduced penetrance. -
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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 highest biochemical and clinical penetrance has been reported in p.(Cys282Tyr) homozygotes (PMID: 20301613). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0252 - This variant is homozygous. (I) 0307 - Variant is present in gnomAD at a frequency >=0.05 (v2: 8992 heterozygotes, 276 homozygotes). (SB) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated IgC MHC I alpha3 functional domain (NCBI). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has previously been described as pathogenic in multiple patients with haemochromatosis (ClinVar; PMIDs: 37260121, 9162021, 19159930); either in a homozygous state or in trans with NP_000401.1(HFE):p.(His63Asp). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis using transfected cell lines showed defects in HFE protein intracellular transport and cell surface expression (PMID: 9162021). (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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Criteria applied: PS3,PM3_STR,PP3,PP4 -
The missense variant c.845G>A(p.Cys282Tyr) in HFE gene has been reported in homozygous state in multiple individuals affected with hemochromatosis (Porto G et. al., 2016; Gallego et. al., 2015). Experimental studies have shown that this missense change disrupts a disulfide bond in the α3 domain of the HFE protein and impairs interaction of HFE with beta2-microglobulin, resulting in a block in intracellular transport and loss of cell surface expression of the Cys282Tyr variant protein (Waheed et. al., 1997). The observed variant has allele frequency of 3.3% in gnomAD exomes database. This variant has been submitted to the ClinVar database as risk factor / Uncertain Significance / Pathogenic (multiple submissions). The reference amino acid change p.Cys282Tyr in HFE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 282 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
PM3_VeryStrong+PS3 -
This sequence change in HFE is predicted to replace cysteine with tyrosine at codon 282, p.(Cys282Tyr). The cysteine residue is highly conserved (100 vertebrates, UCSC), and alters a critical cysteine residue involved in a disulfide bond in the Ig-like C2 type domain and prevents HFE protein presentation (PMID: 20301613). There is a large physicochemical difference between cysteine and tyrosine. The highest population minor allele frequency in the population database gnomAD v2.1 is 5.6% (7,345/128,950 alleles, 243 homozygotes) in the European non-Finnish population. This variant is reported as the common cause of HFE-related haemochromatosis. It has been reported in multiple individuals with haemochromatosis who were either homozygous or compound heterozygous for the variant (PMID: 19159930, 32153640, 11903354). The variant has been reported to segregate with haemochromatosis in multiple affected individuals from unrelated families (PMID: 10575540, 27518069). In vitro functional assays with limited validation showed a significant impairment to protein trafficking and accelerated protein degradation indicating that this variant impacts protein function (PMID: 9162021, 9356458). A transgenic mouse model for the variant showed an increased predisposition to iron loading (PMID: 10381492). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.872). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: BS1, PM3_VeryStrong, PM1, PP1_Strong, PP3, PS3_Moderate. -
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The HFE c.845G>A (p.C282Y) variant is a pathogenic variant observed in 3.4% of the human population (gnomAD). Individuals that are homozygous for the p.C282Y variant have a greater risk of developing iron overload compared to individuals with compound heterozygous variants (i.e. c.845G>A p.C282Y and c.187C>G p.H63D in trans) (PMID: 20301613). -
The c.845G>A (p.Cys282Tyr) missense variant is widely recognized as one of the two most common disease-causing variants in the HFE gene. Cys282Tyr homozygotes account for 80-85% of typical patients with Hereditary Hemochromatosis (HH). However, the majority of individuals who are homozygous for this variant do not develop the disease (GeneReviews, Kowdley et al., 2012; Ramrakhiani and Bacon, 1998; and Morrison et al., 2003). In summary, this variant c.845G>A (p.Cys282Tyr) meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -
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The variant NM_000410.4:c.845G>A (chr6:26092913) in HFE was detected in 7331 heterozygotes and 264 homozygotes out of 58K WGS Icelanders (MAF= 6,775%). Following imputation in a set of 166K Icelanders (710 imputed homozygotes) we observed an association with hemochromatosis under a recessive model using 2403 cases and 240747 controls (OR= 50.27, P= 2.69e-212). This variant has been reported multiple times in ClinVar as pathogenic. Based on ACMG criteria (PS3, PS4, PP1, PP4, PP5) this variant classifies as pathogenic. -
not provided Pathogenic:9Other:1
Common pathogenic variant associated with hereditary hemochromatosis (PMID: 23953397, 8696333); Published functional studies demonstrate a damaging effect as C282Y results in a protein that does not reach the cell surface and is subject to accelerated degradation (PMID: 21243428, 9356458); This variant is associated with the following publications: (PMID: 9356458, 23792061, 32153640, 34490613, 26474245, 29969830, 23953397, 19084217, 19159930, 19271219, 20117027, 19176287, 24604426, 12707220, 22693327, 19258483, 20031541, 20031565, 9836708, 23121079, 20640879, 20946107, 22531912, 23178241, 20099304, 22611049, 20669231, 19820015, 21785125, 23222517, 21514009, 19429178, 22209421, 23281741, 20560808, 17450498, 8696333, 26501199, 27661980, 27659401, 26365338, 25916738, 27153395, 25767899, 11903355, 29555771, 30291871, 30374069, 15254010, 31019283, 31028937, 31640930, 29301508, 25287020, 32189932, 31447099, 30145563, 31980526, 26893171, 32228506, 34426522, 9630070, 9674544, 11336458, 11478530, 11531973, 11976822, 9382962, 10520044, 32641076, 11565552, 9858243, 19912313, 10792295, 11181289, 10090890, 11500063, 11189980, 32874917, 37937776, 27816425, 37443404, 38195192, 28399358, 29145899, 35499102, 27784128, 21243428) -
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HFE: PM3:Very Strong, PS3, PM2:Supporting -
The HFE p.Cys282Tyr variant is a common variant known to cause hereditary hemochromatosis; over 80% of hereditary hemochromatosis patients are homozygous for the p.C282Y variant (Feder_1996_PMID:8696333; Morrison_2003_PMID:12693884). The variant was identified in dbSNP (ID: rs1800562), in ClinVar (classified as pathogenic 13 times, likely pathogenic once and as a VUS once) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 9544 of 282608 chromosomes (276 homozygous) at a frequency of 0.033771 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 7435 of 128950 chromosomes (freq: 0.05766), Other in 281 of 7224 chromosomes (freq: 0.0389), European (Finnish) in 879 of 25108 chromosomes (freq: 0.03501), Latino in 494 of 35430 chromosomes (freq: 0.01394), Ashkenazi Jewish in 124 of 10366 chromosomes (freq: 0.01196), African in 260 of 24962 chromosomes (freq: 0.01042), South Asian in 68 of 30616 chromosomes (freq: 0.002221), and East Asian in 3 of 19952 chromosomes (freq: 0.00015). The p.Cys282 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Functional studies of the p.C282Y variant have demonstrated abnormal protein interaction, expression, processing and localization (Feder_1997_PMID:9162021; Waheed_1997_PMID:9356458). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
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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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Hereditary hemochromatosis Pathogenic:2Other:2
Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 11/20/2019 by Illumina and 6/19/2020 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. -
Variant classified as Pathogenic and reported on 05-24-2022 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
The c.845G>A;p.(Cys282Tyr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 9; OMIM: 613609.0001; PMID: 20301613; 27659401; 26365338; 19084217; 11040194; 23953397; 26365338) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11040194; 23953397; 9162021; 9356458) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Immunoglobulin C1-set domain) - PM1. The p.(Cys282Tyr) was detected in trans with a pathogenic variant (PMID: 15507752; 17384005; 26244503; 25850353; 25277871; 24401005; 23953397; 32153640; 11478530; 26365338) - PM3_very strong The variant co-segregated with disease in multiple affected family members (PMID: 32153640; 11478530) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 282 of the HFE protein (p.Cys282Tyr). This variant is present in population databases (rs1800562, gnomAD 6%), and has an allele count higher than expected for a pathogenic variant. This is a common, low penetrance variant that is known to contribute to hemochromatosis when homozygous or present with a second pathogenic allele in HFE. As many as 90% of individuals of European descent who are affected with hemochromatosis are homozygous for this variant (PMID: 16132052, 26153218, 26365338). ClinVar contains an entry for this variant (Variation ID: 9). 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) indicates that this missense variant is expected to disrupt HFE protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change disrupts a disulfide bond in the α3 domain of the HFE protein and impairs interaction of HFE with beta2-microglobulin, resulting in a block in intracellular transport and loss of cell surface expression of the Cys282Tyr variant protein (PMID: 9162021, 9356458). 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). -
HFE-related disorder Pathogenic:2
The HFE c.845G>A variant is predicted to result in the amino acid substitution p.Cys282Tyr. In patients with transferrin-iron saturation higher than 45%, presence of the c.845G>A (p.Cys282Tyr) variant is useful in confirmation of hereditary hemochromatosis diagnosis as individuals homozygous for the variant represent 80% of cases (Bacon et al. 2011. PubMed ID: 21452290; Alexander and Kowdley. 2009. PubMed ID: 19444013; Kowdley et al. 2012. PubMed ID: 22395570). The c.845G>A (p.Cys282Tyr) variant is incompletely penetrant with ~35% of individuals homozygous for the variant having normal ferritin levels (Bacon et al. 2011. PubMed ID: 21452290). This variant is interpreted as pathogenic. -
PS3, PM3_Very Strong, PP3 -
Inborn genetic diseases Pathogenic:1
The c.845G>A (p.C282Y) alteration is located in coding exon 4 of the HFE gene. This alteration results from a G to A substitution at nucleotide position 845, causing the cysteine (C) at amino acid position 282 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of 3.38% (9544/282608) total alleles studied. The highest observed frequency was 5.77% (7435/128950) of European (non-Finnish) alleles. This alteration is the most common cause of hereditary hemochromatosis (Allen, 2008). In homozygous individuals, up to 50% may develop iron overload, with 10-33% developing hemochromatosis-associated morbidity (EASL, 2010). Men appear to have a higher risk for disease development than women. In homozygous men, 84% display elevated transferrin-iron saturation and 88% have elevated serum ferritin concentration. In comparison, fewer homozygous women have elevated transferrin-iron saturation and serum ferritin concentration (73% and 57%, respectively). However, when p.C282Y is compound heterozygous with another pathogenic alteration, disease penetrance is significantly lower (Adams, 1997). This amino acid position is highly conserved in available vertebrate species. Functional studies have shown that this alteration leads to impaired intracellular transport of the protein and degradation before reaching the cell surface (Feder, 1997; Waheed, 1997). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Cardiomyopathy Pathogenic:1
PS3, PP5, PS4, PM3 -
Abdominal pain;C0004941:Atypical behavior;C0030193:Pain;C0031117:Peripheral neuropathy;C0497552:Abnormality of the nervous system;C4023819:Abnormality of the male genitalia;C4025831:Abnormal peripheral nervous system morphology Pathogenic:1
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Variegate porphyria;C0268323:Familial porphyria cutanea tarda;C1863052:Alzheimer disease type 1;C2673520:Microvascular complications of diabetes, susceptibility to, 7;C3280096:TRANSFERRIN SERUM LEVEL QUANTITATIVE TRAIT LOCUS 2;C3469186:Hemochromatosis type 1 Pathogenic:1
HFE NM_000410.3 exon 4 p.Cys282Tyr (c.845G>A): This variant has been reported in the literature in the homozygous or compound heterozygous state in many individuals with hereditary hemochromatosis (HH) (Allen 2008 PMID:18199861, Pederson 2009 PMID:19159930, Cezard 2014 PMID:23953397, Gallego 2015 PMID:26365338) and is reported to be the most common cause of HH (Le Gac 2005 PMID:16132052, Gallego 2015 PMID:26365338, Porto 2016 PMID:26153218). This variant is present in 3.3% (9544/282608) of total alleles in the Genome Aggregation Database, including 276 homozygotes (https://gnomad.broadinstitute.org/variant/6-26093141-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:9). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, an in vivo mouse study showed postnatal iron loading in mice homozygous for this variant (Levy 1999 PMID:10381492), and in vitro functional studies have shown that the mutant protein is retained in the ER and is unable to interact with beta2-microglobulin (Feder 1997 PMID:9162021, Waheed 1997 PMID:9356458). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -
Hereditary cancer-predisposing syndrome Pathogenic:1
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Porphyrinuria;C0349506:Cutaneous photosensitivity Uncertain:1
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Juvenile hemochromatosis Other:1
HFE c.845G>A (p.Cys282Tyr) has been associated with increased risk for hemochromatosis. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (5.7%, Genome Aggregation Database (gnomAD); rs1800562) and is present in ClinVar (ID: 9). A large meta-analysis has reported an odds ratio of 1.2 [95% CI 0.8-1.6] for developing liver disease in heterozygous carriers (Ellervik 2007). In vitro and in vivo functional studies provide some evidence that this variant may impact protein function (Ali-Rahmani 2011, Boucherma 2012). In summary, this variant is uncertain risk allele for hemochromatosis in heterozygous state. HFE c.845G>A (p.Cys282Tyr) has been associated with increased risk for hemochromatosis. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (5.7%, Genome Aggregation Database (gnomAD); rs1800562) and is present in ClinVar (ID: 9). A large meta-analysis has reported an odds ratio of 3.9 [95% CI 1.9-8.1] for developing liver disease in homozygous carriers (Ellervik 2007). In vitro and in vivo functional studies provide some evidence that this variant may impact protein function (Ali-Rahmani 2011, Boucherma 2012). In summary, this variant is established risk allele for hemochromatosis in homozygous state. -
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