ClinVar Genomic variation as it relates to human health

Vomiting (present) , Vesicoureteral reflux (present) , Thin upper lip vermilion (present) , Sparse eyebrow (present) , Prominent fingertip pads (present) , Neurodevelopmental abnormality (present) , Low-set ears (present) , Joint laxity (present) , Hypertelorism (present) , Horseshoe kidney (present) , Failure to thrive (present) , Abnormal eyelid morphology (present) (less)

This mutation has also been called LYS329GLU (K329E), based on the precursor protein. In 9 patients with MCAD deficiency (ACADMD; 201450), Matsubara et al. (1990) identified an A-to-G transition in the ACADM gene, which resulted in the substitution of lysine (AAA) by glutamic acid (GAA) at residue 329 (K304E) of the enzyme. These patients were unrelated, suggesting a high instance of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. Matsubara et al. (1990) found this point mutation in 31 of 34 (91%) mutant MCAD alleles. In 3 patients with MCAD deficiency, Yokota et al. (1990) demonstrated an A-to-G transition at position 985 (G985) of the coding region of the ACADM gene, which resulted in a lys304-to-glu (K304E) substitution in the mature protein. Since no appropriate restriction sites for detecting this point mutation were found, they devised an ingenious PCR-based method for demonstrating the G985 mutation. In studies of 9 MCAD deficient patients, homozygosity for this mutation was found in all; in contrast, all 8 controls lacked the mutation. All the patients were Caucasian. In a later study, Yokota et al. (1990) found that the mutation introduces a new NcoI restriction site. Genomic DNA from 11 unrelated MCAD patients was homozygous for the G985 transition as indicated by complete cleavage of PCR-amplified fragments by NcoI. The high prevalence of this mutation in Caucasians and the similarity between the mutations described by Yokota et al. (1990) and Matsubara et al. (1990) suggested that the distinction may lie simply in the numbering of residues and that in fact the investigators had described the same mutation. (Residue 304 in the mature human MCAD corresponds to residue 329 in the preprotein.) Yokota et al. (1990) stated that only 3 patients overlapped in their study and that of Matsubara et al. (1990). In a Dutch MCAD-deficient patient described by Duran et al. (1986), Kelly et al. (1990) found an A-to-G change at nucleotide 985 of the MCAD mRNA coding region, resulting in substitution of glutamic acid for lysine at amino acid 304 of the mature protein. In addition to the point mutation, a significant proportion of the index patient's MCAD mRNA contained a variety of deletions and insertions as a result of exon skipping and intron retention. The missplicing occurred in multiple regions throughout the MCAD mRNA. Analysis of regions where missplicing occurred most frequently did not reveal a mutation in the splice acceptor or donor sites. That the lys304-to-glu mutation was pathogenic was supported by the fact that the change was not found in any wildtype MCAD mRNAs. Using a PCR-based test on consecutive Guthrie spots, Blakemore et al. (1991) studied the frequency of the G985 MCAD mutation in the neonatal population of the Trent (England) health region. Although no homozygotes were found, 6 of 410 newborns were heterozygous for the mutation, representing a carrier frequency of 1 in 68. This suggests that the frequency of homozygotes should be about 1 in 18,500 births. Since about 15% of mutations are other than the G985 mutation, the total carrier frequency may be 1 in 58, with the total population frequency 1 in 13,400. Gregersen et al. (1991) found the same mutation in homozygous form in 12 of 13 patients with MCAD deficiency. Gregersen et al. (1991) later reported that 15 of 16 patients with MCAD deficiency were homozygous for the G985 mutation. The same 15 who were homozygous for G985 were also homozygous for the haplotype 112, suggesting founder effect. Kolvraa et al. (1991) found the G985 mutation in 31 of 32 disease-causing alleles. In at least 30 of the 31 alleles carrying this G985 mutation, a specific RFLP haplotype was found. In contrast, the same haplotype was present in only 23% of normal alleles. The findings were interpreted as consistent with a strong founder effect. Curtis et al. (1991) studied 21 affected children from 18 families in the U.K. In 14 families the children were homozygous for the G985 mutation. In 3 families the children were compound heterozygotes for G985 and another unknown mutation. In 1 family the affected child did not carry the G985 on either chromosome. It was calculated that the carrier incidence of the G985 mutation is 1 in 68. In a study of 55 MCAD-deficient patients, Yokota et al. (1991) reported that the G985 allele was found in homozygous state in 44 and in heterozygous state in 10; one patient did not carry this mutant allele, indicating that the prevalence of the G985 allele was 89.1%. They identified 5 other types of mutations: one each in 3 of the compound heterozygotes and 2 in the single non-G985 patient. A RFLP study of 12 G985-homozygotes showed that all 24 alleles fell into a single haplotype. All of 41 patients for whom information was available were Caucasians. Of 29 patients whose country of origin was specified, 19 were from the British Isles and 5 from Germany. Yokota et al. (1991) interpreted these data to indicate that the G985 mutation may have occurred in a single person in an ancient Germanic tribe. Ding et al. (1991) analyzed DNA from 7 infants who had died suddenly of unexpected causes, i.e., cases of sudden infant death syndrome (SIDS; 272120). These cases were identified through the diagnosis of MCAD deficiency in subsequent, live sibs. Mutational analysis performed on postmortem fixed tissue showed the A-to-G mutation at nucleotide 985 in homozygous form in all 7 probands and in heterozygous form in all parents. The fixed tissues had been stored for as long as 18 years. Miller et al. (1992) extracted DNA from autopsy tissues of 67 victims of SIDS in Monroe County, N.Y., who died between 1984 and 1989. Using the PCR/NcoI digestion method, they found no G985 homozygotes and 3 (4.5%) G985 heterozygotes. In 70 newborn controls, they found no G985 homozygotes and 1 (1.4%) heterozygote. They doubted that the G985 mutation is strongly associated with SIDS. Opdal et al. (1995) found no case of the G985 mutation among 133 cases of SIDS, 6 cases of borderline SIDS, and 30 cases of infectious death in Norway. Leung et al. (1992) described an affected neonate in whom lethargy and hypotonia developed at 46 hours of age and death followed 10 hours later. They claimed that neonatal presentation had been ignored or discounted in literature reviews. Matsubara et al. (1991) determined the prevalence of the K304E mutation by study of dried blood spots on Guthrie cards obtained in neonatal screening programs. Twelve carriers were identified among 479 newborn babies in Britain, 5 among 353 in Australia, 5 among 536 in North America, but none among 500 samples in Japan. Gregersen et al. (1991) described a PCR-based assay suitable for use with Guthrie spots. See Matsubara et al. (1992) for a review. Yokota et al. (1992) estimated that 90% of MCAD cases involve a substitution of lysine-329 in the precursor (lysine-304 in the mature protein). Yokota et al. (1992) used site-directed mutagenesis to produce 3 variant cDNAs encoding variant precursor MCAD with glutamate, aspartate, or arginine substituted for lys329. They carried out in vitro expression studies of the cDNAs, and incubated the translation products with isolated rat liver mitochondria. K329E precursor was imported into mitochondria and processed into the mature subunit as efficiently as wildtype, but 10 minutes after import markedly more K329E eluted as a monomer than did wildtype, and the amount of K329E tetramer formed was distinctly less than wildtype at any point up to 60 minutes after import, indicating that the assembly of K329E was defective. After further incubation, K304E decayed more rapidly than did wildtype, indicating a reduced stability. In similar studies K329R behaved like the wildtype, while K329D closely resembled K329E, indicating that a basic residue at 304 is essential for tetramer formation and intramitochondrial stability of mature MCAD. Gregersen et al. (1993) found that the frequency of G985 heterozygotes in Caucasians in North Carolina is 1 in 84 (there are many Scottish-Irish in North Carolina), which is 5- to-10-fold higher than the frequency found in non-Caucasian Americans. They also found a complete association of the G985 mutation in 17 families with a certain haplotype. The frequency of G985 mutation carriers was 1 in 68 to 1 in 101 in newborns in the United Kingdom and Denmark, but 1 in 333 in Italy. They interpreted this as indicating a founder effect in northwestern Europe. A prevalence of carriers of 1 in 55 was estimated by de Vries et al. (1996) on the basis of study of Guthrie cards of newborns. Comparably, the glu510-to-gln mutation of the HADHA gene (600890.0001) is responsible for some 87% of cases of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (IJlst et al., 1996). Wang et al. (1999) provided data on the frequency of the K304E mutation in 20 countries. Of patients clinically diagnosed with MCADD, 81% had been identified retrospectively as homozygous for K304E, and 18% were compound heterozygotes for K304E. The frequency varied from 1 in 6,400 in Birmingham, England, and 1 in 10,000 in Finland to 1 in 442,000 in Italy. In 7 newborns, Andresen et al. (2001) found compound heterozygosity for a 199T-C transition in exon 3 of the ACADM gene, causing a tyr42-to-his substitution. This mutation had never been observed in clinically manifest disease, but was present in a large proportion of the acylcarnitine-positive samples. Overexpression Screening programs employing analysis of acylcarnitines in blood spots by tandem mass spectrometry (MS/MS) are widely used for screening for MCAD deficiency. Andresen et al. (2001) performed mutation analysis in blood spots from 930,078 neonates in the U.S. and found a frequency of MCAD deficiency of 1 in 15,001. Mutation analysis showed that the frequency of the 985A-G mutant allele in newborns with a positive acylcarnitine profile was much lower than that observed in clinically affected patients. In 4 asymptomatic sibs, Albers et al. (2001) reported compound heterozygosity for an arg256-to-thr substitution (607008.0013) with K304E. Bodman et al. (2001) reported a 12-month-old child who presented with viral infections and lethargy and was found to be homozygous for the 985A-G mutation. Family history revealed that his father had experienced episodes of hypoglycemic shock, and genetic analysis showed that he also was homozygous for the mutation. The authors noted that the carrier frequency for the mutation is as common as 1 in 55 persons, which predicts a homozygote frequency of 1 in 12,000. Nichols et al. (2008) found that the K304E mutation accounted for only 47.5% of mutant ACADM alleles in New York state over an 18-month period of newborn screening. The frequency was lower than that reported by others, possibly reflecting the mixed ethnic composition of the New York population. Y42H (607008.0011) was the second most common mutation, accounting for 7.5% of mutant alleles. In a meta-regression analysis of 43 studies reporting the frequency of the c.985A-G mutation in over 10 million individuals, Leal et al. (2014) found significant variation in the frequency of the mutation across regions. The proportion of individuals homozygous for the mutation was highest in western Europe (4.1 per 100,000), followed by the New World, including the United States, Canada, and Australia (3.2), southern Europe (1.2), and eastern Europe (0.9). No cases with the mutation were identified in Asia or the Middle East. The findings were consistent with a founder effect originating in northern Europe. (less)

Premature birth (present) , Prenatal maternal abnormality (present) , Obesity (present) , Overgrowth (present) , Hyperthyroidism (present) , Abnormality of the optic nerve (present) , Myopia (present) , Abnormality of vision (present) , Vertigo (present) , Hyperacusis (present) , Seizures (present) , Generalized hypotonia (present) , EEG abnormality (present) , Cognitive impairment (present) , Short attention span (present) , Obsessive-compulsive behavior (present) , Autistic behavior (present) , Hyperhidrosis (present) , Abnormality of the musculature of the pelvis (present) , Hypercholesterolemia (present) , Hypertension (present) , Cardiomyopathy (present) , Abnormal EKG (present) , Gastrointestinal dysmotility (present) (less)