ClinVar Genomic variation as it relates to human health

Functional abnormality of the bladder (present) , Bloody diarrhea (present) , Aganglionic megacolon (present) , Chest pain (present) , Abnormal peripheral nervous system morphology (present) , Peripheral neuropathy (present) , Hand tremor (present) , EMG abnormality (present) , Abnormality of muscle physiology (present) , Abnormality of peripheral nerve conduction (present) , Stuttering (present) , Anxiety (present) , Behavioral abnormality (present) , Depressivity (present) , Tinnitus (present) , Pes cavus (present) , Abnormality of the foot (present) , Hammertoe (present) , Peripheral axonal neuropathy (present) , Skeletal muscle atrophy (present) , Generalized hypotonia (present) , Hemiparesis (present) , Back pain (present) , Chronic pain (present) , Hernia (present) , Abnormality of the male genitalia (present) , Urinary urgency (present) , Abnormality of the nervous system (present) , Movement disorder (present) , Muscle weakness (present) , Abnormality of peripheral nerves (present) , Foot pain (present) , Knee pain (present) , Pain (present) , Acroparesthesia (present) , Clumsiness (present) , Incoordination (present) , Abdominal pain (present) , Nausea (present) , Allergic rhinitis (present) , Headache (present) , Brisk reflexes (present) , Weight loss (present) , Blotching pigmentation of the skin (present) , Gait disturbance (present) , Postural instability (present) , Gait imbalance (present) , Epididymitis (present) , Orchitis (present) , Dysuria (present) , Scrotal pain (present) (less)

This variant has been reclassified as a polymorphism because the C282Y variant is present in the gnomAD database (v2.1.1) in 9,544 of 282,608 alleles and in 276 homozygotes, with an allele frequency of 0.03377 (Hamosh, 2023). Drakesmith et al. (2002) used a numbering system beginning from the first amino acid of the mature protein, omitting the 22 amino acids of the signal sequence, so that C282 of the immature protein is C260 of the mature protein. Hemochromatosis, Type 1 In patients with hemochromatosis (HFE1; 235200), Feder et al. (1996) identified an 845G-A transition in the HFE gene (which they referred to as HLA-H or 'cDNA 24'), resulting in a cys282-to-tyr (C282Y) substitution. This missense mutation occurs in a highly conserved residue involved in the intramolecular disulfide bridging of MHC class I proteins, and could therefore disrupt the structure and function of this protein. Using an allele-specific oligonucleotide-ligation assay on their group of 178 patients, they detected the C282Y mutation in 85% of all HFE chromosomes. In contrast, only 10 of the 310 control chromosomes (3.2%) carried the mutation, a carrier frequency of 10/155 = 6.4%. One hundred forty-eight of 178 HH patients were homozygous for this mutation, 9 were heterozygous, and 21 carried only the normal allele. These numbers were extremely discrepant from Hardy-Weinberg equilibrium. The findings corroborated heterogeneity among the hemochromatosis patients, with 83% of cases related to C282Y homozygosity. Jazwinska et al. (1996) provided convincing evidence that the C282Y mutation in homozygous form in the HFE gene is the cause of hemochromatosis. In studies in Australia, patients properly characterized at the genotypic and phenotypic level all showed homozygosity for the C282Y substitution. Irrespective of haplotype, all HH heterozygotes were cys/tyr heterozygotes, and all homozygous normal controls were cys/cys homozygotes. The presence of a single mutation in all patients contrasted with the data of Feder et al. (1996), who reported a lower frequency of the mutation. Jazwinska et al. (1996) suggested that different clinical criteria for the diagnosis of HH may account for the difference, or that HH may not be as homogeneous as previously believed. They noted that a key question is why there is a variation in severity of iron loading in HH that is haplotype-related when the mutation is identical in all haplotypes tested. Jazwinska et al. (1996) hypothesized that the HFE locus is the primary HH locus, but that there are likely to be other 6p-linked modifying genes that would explain both the HLA-linked haplotype variation in expression of the disorder and the large region of linkage disequilibrium present in all populations and spanning at least 4.5 Mb distal of D6S265. Jouanolle et al. (1996) commented on the significance of the C282Y mutation on the basis of a group of 65 unrelated affected individuals who had been under study in France for more than 10 years and identified by stringent criteria. Homozygosity for the C282Y mutation was found in 59 of 65 patients (90.8%); 3 of the patients were compound heterozygotes for the C282Y mutation and the H63D mutation (613609.0002); 1 was homozygous for the H63D mutation; and 2 were heterozygous for H63D. These results corresponded to an allelic frequency of 93.1% for the C282Y and 5.4% for the H63D mutations, respectively. Of note, the C282Y mutation was never observed in the family-based controls, whereas it was present in 5.8% of the general Breton population. This corresponds to a theoretical frequency of about 1 per 1,000 for the disease, which is slightly lower than generally estimated. In contrast, the H63D allelic frequency was nearly the same in both control groups (15% and 16.5% in the family-based and general population controls, respectively). While the experience of Jouanolle et al. (1996) appeared to indicate a close relationship of C282Y to hemochromatosis, the implication of the H63D variant was not clear. Beutler et al. (1996) reported mutation analysis of 147 patients with hereditary hemochromatosis and 193 controls; 121 (82.3%) HH patients were homozygous for the C282Y mutation and 10 (6.8%) were heterozygous. All of the C282Y homozygous patients were also homozygous for the wildtype nucleotide 187C (see H63D; 613609.0002), and all C282Y heterozygotes had at least 1 copy of 187C. Thus, the 2 nucleotides, 845 and 187, were in complete linkage disequilibrium; nucleotide 187 was a C on all chromosomes with the 845A (C282Y) mutation. Eight of the 10 heterozygotes for 845A were heterozygous for 187G (H63D). Among 132 unrelated hemochromatosis patients in Brittany, Jouanolle et al. (1997) found that 92% were homozygous for the C282Y mutation and that all 264 chromosomes except 5 carried either the C282Y mutation or the H63D mutation. The UK Haemochromatosis Consortium (1997) genotyped 115 unrelated hereditary hemochromatosis patients and found that 105 (91%) were homozygous for the C282Y mutation. One of 101 controls was also found to be homozygous but was subsequently found to have evidence of iron overload. Compound heterozygosity for the C282Y and H63D mutations was found in 3 patients who had mild disease and in 4 controls who had no signs of iron overload. Five patients lacked either mutation, 2 of whom had atypical, early-onset disease. Feder et al. (1997) confirmed the prediction that the C282Y mutation would disrupt a critical disulfide bond in the alpha-3 loop of the HFE protein and abrogate binding of the mutant HFE protein to beta-2-microglobulin (B2M; 109700), as well as its transport to and presentation on the cell surface. In vitro, the C282Y mutant HFE protein failed to associate with endogenous B2M in human embryonic kidney cells stably transfected with the mutant cDNA. Waheed et al. (1997) found that whereas the wildtype and H63D HFE proteins associate with beta-2 microglobulin and are expressed on the cell surface of COS-7 cells, these capabilities are lost by the C282Y HFE protein. They presented biochemical and immunofluorescence data indicating that the C282Y mutant protein is retained in the endoplasmic reticulum and middle Golgi compartments, fails to undergo late Golgi processing, and is subject to accelerated degradation. The block in intracellular transport, accelerated turnover, and failure of the C282Y protein to be presented normally on the cell surface provides a possible basis for impaired function of this mutant protein in hereditary hemochromatosis. In 478 hemochromatosis probands in Brittany selected from their iron status markers, primarily serum iron, serum ferritin, and transferrin saturation, Mura et al. (1997) investigated the relationships between the hemochromatosis phenotype and genotypes at the HLA-H locus and surrounding markers. They found that the C282Y substitution is unambiguously associated with the hemochromatosis phenotype; 81.2% of all patients were homozygous. The subgroup of heterozygous individuals showed lower values for serum ferritin, transferrin saturation, and iron removed by phlebotomy than did the subgroup of hemochromatosis patients homozygous for C282Y. In the subgroup not homozygous for C282Y, no other mutation in the HLA-H gene was found; hence, the genotype remained unclear. The authors suggested additional nongenetic cause, other mutations, or another gene as explanations for the results in these patients. Rhodes et al. (1997) reported haplotype and mutation analysis in a 3-generation family. Three sibs with overt hemochromatosis, 1 male and 2 females aged 50 to 53 years, showed homozygosity for the C282Y mutation. However, homozygosity for the mutation was detected in an asymptomatic and biochemically normal 50-year-old male sib of the affected individuals. Rhodes et al. (1997) concluded that this finding caused them to question the possibility of population and presymptomatic screening by genetic testing for hemochromatosis. Roth et al. (1997) found no instance of the C282Y substitution in the HFE gene of individuals originating from Algeria, Ethiopia, or Senegal, whereas it is highly prevalent in populations of European ancestry. The geographic distribution supported the previously suggested Celtic origin of hemochromatosis. In contrast, the H63D substitution is not restricted to European populations. Although absent in the Senegalese, it was found on about 9% of the chromosomes of the central Ethiopians and Algerians genotyped for this study. Thus, the H63D substitution must have occurred earlier than the C282Y substitution. Merryweather-Clarke et al. (1997) reported the prevalence of the C282Y and H63D mutations in 2,978 people from 42 different populations worldwide. The authors found the highest frequency of C282Y in northern European populations, consistent with the theory of a north European origin for the mutation. In this report, C282Y was seen rarely in the African, Asian, and Australasian chromosomes studied, while H63D was more widely distributed. Although hemochromatosis is common in Caucasians, affecting more than 1 in 300 individuals of northern European origin, the disorder has not been recognized in other populations. Cullen et al. (1998) used PCR and restriction-enzyme digestion to analyze the frequency of the C282Y and H63D mutations in HLA-typed samples of non-Caucasian populations, comprising Australian Aboriginal, Chinese, and Pacific Islanders. They found that the C282Y mutation was present in these populations (allele frequency 0.32%), and that it was always seen in conjunction with HLA haplotypes common in Caucasians, suggesting that C282Y may have been introduced into these populations by Caucasian admixture. They found the H63D mutation at an allele frequency of 2.68% in the 2 populations analyzed (Australian Aboriginal and Chinese). In the Australian Aboriginal samples, H63D was found to be associated with HLA haplotypes common in Caucasians, again suggesting that it was introduced by recent admixture. In the Chinese samples analyzed, on the other hand, H63D was present in association with a wide variety of HLA haplotypes, showing that this mutation is widespread and likely to predate the more genetically restricted C282Y mutation. In European populations, Lucotte (1998) found the frequency of the C282Y mutation to be 6.88% in Celtics, 6.46% in Nordics, 5.95% in Anglo-Saxons, 2.53% in southern Europeans, and 1.76% in Russians. They believed these findings supported the suggestion concerning the Celtic origin of the mutation. Celtic origin of the mutation was also supported by the finding of Ryan et al. (1998) of a 14% carrier frequency of the C282Y allele in Ireland, the highest frequency reported to the time of report. Jeffrey et al. (1999) identified a single nucleotide polymorphism (5569G-A; 613609.0004) in intron 4 of the HFE gene that caused overestimation of C282Y homozygote prevalence in hemochromatosis. Beutler et al. (2002) screened 41,038 individuals attending a health appraisal clinic in the U.S. for the C282Y and H63D (613609.0002) HFE mutations, and analyzed laboratory data on signs and symptoms of hemochromatosis as elicited by questionnaire. The most common symptoms of hemochromatosis were no more prevalent among the 152 identified homozygotes than among the controls. The age distribution of homozygotes and compound heterozygotes did not differ significantly from that of controls; there was no measurable loss of such individuals from the population during aging. However, there was a significantly increased prevalence of a history of hepatitis or 'liver trouble' among homozygotes and in the proportion of homozygotes with increased concentrations of serum aspartate aminotransferase and collagen IV; these changes were not related to iron burden or to age. Only 1 of the 152 homozygotes had signs and symptoms that would suggest a diagnosis of hemochromatosis. Beutler et al. (2002) concluded that the penetrance of hereditary hemochromatosis is much lower than generally thought. They estimated that less than 1% of homozygotes develop frank clinical hemochromatosis. Poullis et al. (2002) concluded that Beutler et al. (2002) underestimated the penetrance of the C282Y HFE mutation. The immigration of Hispanic and Asian populations into southern California may have influenced the frequency. Within South Wales, McCune et al. (2002) performed a systematic review of patients with HH over a 2-year period which revealed that only 1.2% of adult C282Y homozygotes had been diagnosed with iron overload and received treatment. In those in whom body iron load could be estimated, only 51% had more than 4 grams of iron (the diagnostic threshold for iron overload). McCune et al. (2002) stated that screening the general UK population by genetic testing could identify thousands of individuals homozygous for the C282Y mutation, but the majority would not express a phenotype leading to a diagnosis of HH and would likely remain healthy. They concluded that until the cofactors determining disease expression were more fully understood, the benefits of such screening, both to the individual and to the community, would likely be outweighed by the costs. Andersen et al. (2004) undertook to determine the progression rate of iron overload in hereditary hemochromatosis in individuals in the general population, and to answer the question of how frequently asymptomatic C282Y homozygotes identified in the population need to be screened for manifestations of hemochromatosis in later years. As a function of biologic age, transferrin saturation and ferritin levels increase slightly in male and female C282Y homozygotes. None of the C282Y homozygotes developed clinically overt hemochromatosis. The authors concluded that most such homozygotes need to be screened for manifestation of hemochromatosis every 10 to 20 years. Saric et al. (2006) estimated the frequency of the C282Y mutation to be 1.6% in the population of Serbia and Montenegro. The authors noted that the frequency of C282Y decreases going from northwest to southeast Europe, consistent with a Viking or Celtic origin. Livesey et al. (2004) analyzed the presence of the common mtDNA 16189T-C variant, which appears to be a risk factor for type 2 diabetes (125853), in British, French, and Australian C282Y homozygotes and controls, with known iron status, and in birth cohorts. The frequency of the 16189 variant was found to be elevated in individuals with hemochromatosis who were homozygous for the C282Y allele, compared with population controls and with C282Y homozygotes who were asymptomatic. They concluded that iron loading in C282Y homozygotes with hemochromatosis was exacerbated by the presence of the 16189 variant. Allen et al. (2008) reported on a study of HFE mutations in 31,192 persons of northern European descent between ages 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1,438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), they obtained clinical and biochemical data, including 2 sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. The proportion of C282Y homozygotes with documented iron overload-related disease was 28.4% for men and 1.2% for women. Only 1 non-C282Y homozygote (a compound heterozygote with his63 to asp) had documented iron overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1,000 micrograms per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wildtype gene. Waalen and Beutler (2008) and Rienhoff (2008) commented that the study by Allen et al. (2008) may have overestimated the clinical prevalence and penetrance of iron-overload disease in C282Y homozygotes. Levy et al. (1999) produced 2 mutations in the murine Hfe gene. The first mutation deleted a large portion of the coding sequence, generating a null allele. The second mutation introduced the C282Y change into the Hfe gene but otherwise left the gene intact. Homozygosity for either mutation resulted in postnatal iron loading. The effects of the null mutation were more severe than the effects of the C282Y mutation. The mice heterozygous for either mutation accumulated more iron than normal controls. Although liver iron stores were greatly increased, splenic iron was decreased. Levy et al. (1999) concluded that the C282Y mutation does not result in a null allele. Hemochromatosis, Juvenile Merryweather-Clarke et al. (2003) reported an individual with a juvenile hemochromatosis (602390) phenotype who was heterozygous for the C282Y mutation in the HFE gene as well as a 4-bp HAMP frameshift mutation (606464.0003). In another family, they found the C282Y mutation in HFE together with a G71D mutation in HAMP (606464.0004). There was a correlation between severity of iron overload, heterozygosity for a G71D HAMP mutation, and heterozygosity or homozygosity for the HFE C282Y mutation. Porphyria Cutanea Tarda Roberts et al. (1997) analyzed 41 patients with sporadic porphyria cutanea tarda and 101 controls for the presence of the C282Y and H63D mutations. They identified the C282Y mutation in 18 (44%) patients compared to 11 (11%) controls (relative risk = 6.2; p = 0.00003); 7 patients were homozygotes. In 12 patients, the C282Y mutation was associated with markers of the HLA-A3-containing ancestral hemochromatosis haplotype. There was no difference in the frequency of the H63D mutation between the 2 groups. Roberts et al. (1997) concluded that inheritance of one or more hemochromatosis genes is an important susceptibility factor for sporadic porphyria cutanea tarda. They noted that some C282Y homozygotes present late in life with porphyria cutanea tarda, indicating that not all homozygotes present clinically with hemochromatosis. Among 8 patients with porphyria cutanea tarda, Mehrany et al. (2004) found that 6 had mutations in the HFE gene: 3 were homozygous for C282Y, 1 was compound heterozygous for C282Y and H63D, and 2 were heterozygous for C282Y. Mehrany et al. (2004) noted that early detection and treatment of hereditary hemochromatosis limits progression of PCT and improves life expectancy. Porphyria Variegata De Villiers et al. (1999) found that the mutant allele frequency of the C282Y mutation was significantly lower in 73 apparently unrelated variegate porphyria (176200) patients with the arg59-to-trp mutation in the PPOX gene (600923.0003) than in 102 controls drawn from the same population (P = 0.005). The authors concluded that the population screening approach used in this study revealed considerable genotypic variation in the HFE gene and supported previous data on involvement of the HFE gene in the porphyria phenotype. Iron overload is a well-established precipitating or aggravating factor in porphyria variegata. Transferrin Serum Level Quantitative Trait Locus 2 In a genomewide association study of Australians of European descent, Benyamin et al. (2009) found that the C282Y variant (rs1800562) was associated with serum iron (p = 3.5 x 10(-11)), serum transferrin (see TFQTL2, 614193) (p = 1.1 x 10(-10)), transferrin saturation (p = 4.3 x 10(-15)), and serum ferritin (see FTH1, 134770) (p = 4.5 x 10(-5)). C282Y explained 9.5%, 9.1%, 13.2%, and 3.7% of the variation in means of serum iron, serum transferrin, transferrin saturation, and serum ferritin levels, respectively. Three SNPs in the TF gene plus the HFE C282Y mutation explained about 40% of genetic variation in serum transferrin (p = 7.8 x 10(-25)). Microvascular Complications of Diabetes 7, Susceptibility to Walsh and Malins (1978) reported an association between diabetic retinopathy (MVCD7; 603933) and idiopathic hemochromatosis. Peterlin et al. (2003) searched for a relationship between the C282Y and H63D gene mutations and the development of proliferative diabetic retinopathy in Caucasians with type 2 diabetes (125853). A significantly higher frequency of C282Y heterozygosity was found in patients with proliferative diabetic retinopathy compared to subjects without it, whereas no association was demonstrated with H63D. Logistic regression analysis revealed that the C282Y mutation was a significant independent risk factor for the development of PDR (odds ratio = 6.1; p = 0.027). Oliva et al. (2004) analyzed the C282Y HFE polymorphism in 225 Spanish patients with type 2 diabetes and detected a younger age of onset and longer duration of disease in patients carrying at least 1 C282Y allele. They also found an increased prevalence of retinopathy (p = 0.014) and of nephropathy (p = 0.04) in individuals carrying at least 1 C282Y allele; the increased prevalence of retinopathy, but not nephropathy, in C282Y carriers was related to increased duration of disease. Multivariate logistic regression analysis confirmed that the prevalence of nephropathy was higher in the group of patients carrying at least 1 Y allele. Davis et al. (2008) analyzed H63D and C282Y HFE genotype data for 1,245 Australian patients with type 2 diabetes from the longitudinal observational Fremantle Diabetes Study and found no independent positive associations between HFE gene status and either microvascular or macrovascular complications in cross-sectional and longitudinal analyses. Alzheimer Disease Robson et al. (2004) noted that there is evidence that iron may play a role in the pathology of Alzheimer disease (104300). Thus, genetic factors that contribute to iron deposition resulting in tissue damage might exacerbate AD. The authors examined the interaction between the C2 variant of the TF gene (190000.0004) and the C282Y allele of the HFE gene, the most common basis of hemochromatosis, as risk factors for developing AD. The results showed that each of the 2 variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. Furthermore, carriers of these 2 alleles plus APOE4 (see 107741) were at still higher risk of AD: of the 14 carriers of the 3 variants identified in this study, 12 had AD and 2 had mild cognitive impairment. Robson et al. (2004) concluded that their results indicated that the combination of TF*C2 and HFE C282Y may lead to an excess of redoxactive iron and the induction of oxidative stress in neurons, which is exacerbated in carriers of APOE4. They noted that 4% of northern Europeans carry the 2 iron-related variants and that iron overload is a treatable condition. (less)

Global developmental delay (present) , Delayed speech and language development (present) , Autistic behavior (present) , Specific learning disability (present) , Poor appetite (present) , Short stature (present) , Delayed skeletal maturation (present) , Premature birth (present) (less)