ClinVar Genomic variation as it relates to human health

Van der Put et al. (1998) identified another polymorphism of the MTHFR gene: a 1298A-C mutation resulting in a glu429-to-ala (E429A) substitution. The mutation destroyed an MboII recognition site and had an allele frequency of 0.33. Whereas the 677C-T transition (607093.0003) occurs within the predicted catalytic domain of the MTHFR enzyme, the 1298A-C transversion is located in the presumed regulatory domain. The 1298A-C mutation resulted in decreased MTHFR activity, which was more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state was associated with higher plasma homocysteine (Hcy) nor a lower plasma folate concentration--phenomena that are evident with homozygosity for the 677C-T mutation. However, van der Put et al. (1998) found that combined heterozygosity at the 2 polymorphic sites was associated with reduced MTHFR-specific activity, higher Hcy, and decreased plasma folate levels. Thus, combined heterozygosity for both MTHFR mutations resulted in features similar to those observed in homozygotes for the 677C-T mutation. This combined heterozygosity was observed in 28% of the neural tube defect (NTD) patients compared with 20% among controls, resulting in an odds ratio of 2.04. The data suggested that combined heterozygosity for the 2 common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677C-T mutation. Yamada et al. (2001) studied the biochemical characteristics of the products of both the 677C-T and the 1298A-C polymorphisms by overexpressing the genes and purifying the protein to homogeneity in quantities suitable for the characterization. The E429A protein had biochemical properties indistinguishable from the wildtype enzyme. The A222V MTHFR, however, had an enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution. Protein that had both changes revealed no additive effect in these biochemical studies. This prompted Scott (2001) to suggest that the claim of van der Put et al. (1998) that the double variant increases risk needed to be reevaluated. Donnelly (2000) argued that the change described by van der Put et al. (1998) as 1298A-C is in fact 1289A-C. The mutation was expected to change the codon from GAA (glu) to GCA (ala). In a reply to Donnelly (2000), van der Put and Blom (2000) stated that the second SNP was designated 1298A-C for consistency with the first SNP, 677C-T. Although the first SNP was said to occur at nucleotide 677, the actual location may be nucleotide 665 of the coding region. Isotalo et al. (2000) analyzed 119 neonatal cord blood samples and 161 fetal tissue samples for MTHFR 677C-T and 1298A-C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis demonstrated that all possible MTHFR genotype combinations were represented in the fetal group; 677T and 1298C alleles could occur in either cis or trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contained 3 and 4 mutant alleles, respectively, were not observed in the neonatal group (p = 0.0402). This suggested decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This was the first report to describe the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrated their potential role in compromised fetal viability. Volcik et al. (2001) presented data supporting the conclusion of Isotalo et al. (2000) concerning decreased viability among fetuses with the 677TT/1298CC genotype, which they did not observe in the United States and Canadian populations studied. Because they observed, in 3 different populations, the 677CT/1298CC genotype in frequencies nearing those expected, Volcik et al. (2001) concluded that this genotype does not result in a significant selective disadvantage. Zetterberg et al. (2002) examined the distribution of the 677C-T and 1298A-C polymorphisms in 80 fetal tissue samples from spontaneous abortions occurring between the sixth and twentieth week of pregnancy, compared to 125 healthy blood donors (both cases and controls were from Crete, Greece). Only 1 of the 80 spontaneously aborted embryos had the wildtype combined genotype 677CC/1298AA as compared to 19 of 125 controls (p = 0.001). Combined genotypes which contain 3 or 4 mutant alleles were not detected in any of the groups, suggesting complete linkage disequilibrium between the 2 polymorphisms. A significant odds ratio of 14.2 (95% CI, 1.78-113) for spontaneous abortion was obtained when comparing the prevalence of at least 1 MTHFR mutation in abortions and controls (p = 0.001). Zetterberg et al. (2002) concluded from the data that the effect of 1 or more MTHFR mutated alleles may be detrimental during embryogenesis when the folate requirement is high. Both the 677C-T and 1298A-C SNPs in the MTHFR gene decrease the activity of the enzyme, leading to hyperhomocysteinemia (603174), particularly in folate-deficient states. Ogino and Wilson (2003) calculated the haplotype frequencies of the polymorphisms at nucleotides 677 and 1298 in pooled general populations derived from data published in 16 articles. They found that most 677T and 1298C alleles were associated with 1298A and 677C alleles, respectively. There may be an increased frequency of the very rare cis 677T/1298C haplotype in some parts of the United Kingdom and Canada, possibly due to a founder effect. Among Turkish women, Boduroglu et al. (2004) could find no support for a relationship between the 677C-T and 1298A-C SNPs in the MTHFR gene and risk of having a child with Down syndrome (190685). Among 200 Indian individuals, Kumar et al. (2005) found that plasma homocysteine levels were significantly increased in those adhering to a vegetarian diet and in those with a 1298C allele. However, the increase in homocysteine levels in vegetarians was irrespective of MTHFR genotype. Among a larger group of over 400 Indian individuals, Kumar et al. (2005) found that the frequency of the 1298CC genotype was 19.46%, which was much higher than that reported for Caucasian (9.4%), Chinese (3.3%), or Japanese (1.6%) populations. The authors concluded that the 1298A-C polymorphism is relevant for increased plasma homocysteine levels in the Indian population. Hobbs et al. (2006) observed an apparent protective effect of the MTHFR 1298C allele against congenital heart defect. Allen et al. (2008) performed a metaanalysis comparing 1,211 cases of schizophrenia with 1,729 controls and found that the MTHFR 1298C allele (1801133) was associated with susceptibility to schizophrenia (odds ratio, 1.19; 95% CI, 1.07- 1.34; p = 0.002). According to the Venice guidelines for the assessment of cumulative evidence in genetic association studies (Ioannidis et al., 2008), the MTHFR association showed a 'strong' degree of epidemiologic credibility. (less)

Van der Put et al. (1998) identified another polymorphism of the MTHFR gene: a 1298A-C mutation resulting in a glu429-to-ala (E429A) substitution. The mutation destroyed an MboII recognition site and had an allele frequency of 0.33. Whereas the 677C-T transition (607093.0003) occurs within the predicted catalytic domain of the MTHFR enzyme, the 1298A-C transversion is located in the presumed regulatory domain. The 1298A-C mutation resulted in decreased MTHFR activity, which was more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state was associated with higher plasma homocysteine (Hcy) nor a lower plasma folate concentration--phenomena that are evident with homozygosity for the 677C-T mutation. However, van der Put et al. (1998) found that combined heterozygosity at the 2 polymorphic sites was associated with reduced MTHFR-specific activity, higher Hcy, and decreased plasma folate levels. Thus, combined heterozygosity for both MTHFR mutations resulted in features similar to those observed in homozygotes for the 677C-T mutation. This combined heterozygosity was observed in 28% of the neural tube defect (NTD) patients compared with 20% among controls, resulting in an odds ratio of 2.04. The data suggested that combined heterozygosity for the 2 common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677C-T mutation. Yamada et al. (2001) studied the biochemical characteristics of the products of both the 677C-T and the 1298A-C polymorphisms by overexpressing the genes and purifying the protein to homogeneity in quantities suitable for the characterization. The E429A protein had biochemical properties indistinguishable from the wildtype enzyme. The A222V MTHFR, however, had an enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution. Protein that had both changes revealed no additive effect in these biochemical studies. This prompted Scott (2001) to suggest that the claim of van der Put et al. (1998) that the double variant increases risk needed to be reevaluated. Donnelly (2000) argued that the change described by van der Put et al. (1998) as 1298A-C is in fact 1289A-C. The mutation was expected to change the codon from GAA (glu) to GCA (ala). In a reply to Donnelly (2000), van der Put and Blom (2000) stated that the second SNP was designated 1298A-C for consistency with the first SNP, 677C-T. Although the first SNP was said to occur at nucleotide 677, the actual location may be nucleotide 665 of the coding region. Isotalo et al. (2000) analyzed 119 neonatal cord blood samples and 161 fetal tissue samples for MTHFR 677C-T and 1298A-C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis demonstrated that all possible MTHFR genotype combinations were represented in the fetal group; 677T and 1298C alleles could occur in either cis or trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contained 3 and 4 mutant alleles, respectively, were not observed in the neonatal group (p = 0.0402). This suggested decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This was the first report to describe the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrated their potential role in compromised fetal viability. Volcik et al. (2001) presented data supporting the conclusion of Isotalo et al. (2000) concerning decreased viability among fetuses with the 677TT/1298CC genotype, which they did not observe in the United States and Canadian populations studied. Because they observed, in 3 different populations, the 677CT/1298CC genotype in frequencies nearing those expected, Volcik et al. (2001) concluded that this genotype does not result in a significant selective disadvantage. Zetterberg et al. (2002) examined the distribution of the 677C-T and 1298A-C polymorphisms in 80 fetal tissue samples from spontaneous abortions occurring between the sixth and twentieth week of pregnancy, compared to 125 healthy blood donors (both cases and controls were from Crete, Greece). Only 1 of the 80 spontaneously aborted embryos had the wildtype combined genotype 677CC/1298AA as compared to 19 of 125 controls (p = 0.001). Combined genotypes which contain 3 or 4 mutant alleles were not detected in any of the groups, suggesting complete linkage disequilibrium between the 2 polymorphisms. A significant odds ratio of 14.2 (95% CI, 1.78-113) for spontaneous abortion was obtained when comparing the prevalence of at least 1 MTHFR mutation in abortions and controls (p = 0.001). Zetterberg et al. (2002) concluded from the data that the effect of 1 or more MTHFR mutated alleles may be detrimental during embryogenesis when the folate requirement is high. Both the 677C-T and 1298A-C SNPs in the MTHFR gene decrease the activity of the enzyme, leading to hyperhomocysteinemia (603174), particularly in folate-deficient states. Ogino and Wilson (2003) calculated the haplotype frequencies of the polymorphisms at nucleotides 677 and 1298 in pooled general populations derived from data published in 16 articles. They found that most 677T and 1298C alleles were associated with 1298A and 677C alleles, respectively. There may be an increased frequency of the very rare cis 677T/1298C haplotype in some parts of the United Kingdom and Canada, possibly due to a founder effect. Among Turkish women, Boduroglu et al. (2004) could find no support for a relationship between the 677C-T and 1298A-C SNPs in the MTHFR gene and risk of having a child with Down syndrome (190685). Among 200 Indian individuals, Kumar et al. (2005) found that plasma homocysteine levels were significantly increased in those adhering to a vegetarian diet and in those with a 1298C allele. However, the increase in homocysteine levels in vegetarians was irrespective of MTHFR genotype. Among a larger group of over 400 Indian individuals, Kumar et al. (2005) found that the frequency of the 1298CC genotype was 19.46%, which was much higher than that reported for Caucasian (9.4%), Chinese (3.3%), or Japanese (1.6%) populations. The authors concluded that the 1298A-C polymorphism is relevant for increased plasma homocysteine levels in the Indian population. Hobbs et al. (2006) observed an apparent protective effect of the MTHFR 1298C allele against congenital heart defect. Allen et al. (2008) performed a metaanalysis comparing 1,211 cases of schizophrenia with 1,729 controls and found that the MTHFR 1298C allele (1801133) was associated with susceptibility to schizophrenia (odds ratio, 1.19; 95% CI, 1.07- 1.34; p = 0.002). According to the Venice guidelines for the assessment of cumulative evidence in genetic association studies (Ioannidis et al., 2008), the MTHFR association showed a 'strong' degree of epidemiologic credibility. (less)