Description
The HADHA c.1528G>C (p.Glu510Gln) variant, commonly known as Glu474Gln, has been reported in at least eight studies in association with HADHA-related disorders, including LCHAD deficiency and trifunctional protein deficiency. Across a selection of the available literature, the variant is found in at least 153 probands including at least 71 in a homozygous state, at least 22 in a compound heterozygous state, and 52 unaffected in a heterozygous state (Ijlst et al. 1994; Ijlst et al. 1997; Olpin et al. 2005; Piekutowska-Abramczuk et al. 2010; Joost et al. 2012; Boutron et al. 2011; Liewluck et al. 2013; Karall et al. 2015). The p.Glu510Gln variant was found in a compound heterozygous state with a premature termination codon on the second allele in at least twelve cases (Boutron et al. 2011). The p.Glu510Gln variant was absent from 110 control chromosomes and is reported at a frequency of 0.004032 in the European (Finnish) population of the Genome Aggregation Database. Functional testing of the p.Glu510Gln variant protein in yeast cells exhibited a loss of 3-hydroxyacyl-CoA dehydrogenase activity compared to wild type (Ijlst et al. 1996). In addition, functional testing in proband-specific retinal pigment epithelial cells found that cells carrying the p.Glu510Gln variant protein in a homozygous state were small, irregular in shape, with decreased pigmentation and had disorganized tight junctions inducing apoptosis (Polinati et al. 2015). Based on the collective evidence, the p.Glu510Gln variant is classified as pathogenic for HADHA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
