ClinVar

Description

The HADHA c.1528G>C; p.Glu510Gln variant (rs137852769) is the most common variant in individuals affected with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, found in either the homozygous or compound heterozygous state (IJlst 1994, reviewed in Piekutowska-Abramczuk 2010). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 100085), and is found in the general population with an overall allele frequency of 0.13% (366/282,830 alleles) in the Genome Aggregation Database. The glutamic acid at codon 510 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show normal protein expression but significant loss of enzyme activity (IJlst 1994, Olpin 2005). Based on available information, the p.Glu510Gln variant is considered to be pathogenic. References: IJlst L et al. Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein. Biochim Biophys Acta. 1994 Dec 8;1215(3):347-50. Olpin SE et al. Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency. J Inherit Metab Dis. 2005;28(4):533-44. Piekutowska-Abramczuk D et al. A comprehensive HADHA c.1528G>C frequency study reveals high prevalence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in Poland. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S373-7.