ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.1528G>C (p.Glu510Gln) (rs137852769)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185933 SCV000226211 pathogenic not provided 2016-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000185933 SCV000238888 pathogenic not provided 2018-07-09 criteria provided, single submitter clinical testing The E510Q missense variant has been identified in approximately60-87% of abnormal HADHA alleles (Boutron, et al., 2011). Introduction of the E510Q pathogenicvariant into S. cerevisiae cells found that is associated with no detectable LCHAD enzyme activity(IJlst et al. 1996).
Myriad Women's Health, Inc. RCV000174836 SCV000485102 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2016-03-10 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000174836 SCV000538038 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing This c.1528G>C (p.Glu510Gln) variant has been identified in individuals affected with LCHAD deficiency and described, in the homozygous state, as the major disease-causing mutation in the alpha subunit of the mitochondrial trifunctional protein (IJlst et al. 1994). This variant is located in the catalytic site of the LCHAD domain. Functional studies show that although this variant results in intact mutant protein, its LCHAD activity is significantly reduced (Olpin et al. 2005). It is absent or not frequent in the population databases (0% in 1000 genomes and Exome Sequencing Project, and 0.18% in ExAc) and several computational algorithms predict this variant as deleterious. It has also been reported pathogenic by reputable mutation databases (ClinVar, Emory Genetics Laboratory, and HGMD). In sum, this c.1528G>C (p.Glu510Gln) variant is best described as a recessive pathogenic variant for LCHAD deficiency.
Genetic Services Laboratory, University of Chicago RCV000504332 SCV000595089 pathogenic LCHAD Deficiency 2016-11-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000535911 SCV000611201 pathogenic Mitochondrial trifunctional protein deficiency; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000535911 SCV000645773 pathogenic Mitochondrial trifunctional protein deficiency; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 510 of the HADHA protein (p.Glu510Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs137852769, ExAC 0.3%). This variant has been reported most commonly as homozygous but also in combination with another HADHA variant in multiple individuals and families affected with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency or mitochondrial trifunctional protein deficiency (PMID: 7811722, 20583174, 19852779, 26653362, 25888220, 15902556, 23868323, 27491397, 18408953, 21103935, 11773547, 14630990, 26109258, 8739956, 21549624). This variant is also known as p.Glu474Gln or p.E474Q in the literature. ClinVar contains an entry for this variant (Variation ID: 100085). Experimental studies have shown that this missense change results in normal protein expression but a significant loss of long-chain 3-hydroxyacyl-CoA dehydrogenase activity (PMID: 15902556, 8770876, 14630990). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000174836 SCV000695940 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2016-08-29 criteria provided, single submitter clinical testing Variant summary: The HADHA c.1528G>C (p.Glu510Gln) variant involves the alteration of a conserved nucleotide. This variant is located at a highly conserved amino acid (Glu510) in the NAD(P)-binding domain, and 4/5 in silico tools predict a damaging outcome for this variant. Homozygous patient fibroblasts show that this variant results in LCHAD activity <10% of normal. This variant was found in 146/121410 control chromosomes at a frequency of 0.0012025, which does not exceed the estimated maximal expected allele frequency of a pathogenic HADHA variant (0.0019365). The variant has been reported in many LCHAD patients in homozygous and compound heterozygous state as a commonly known pathogenic variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000624767 SCV000740753 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Illumina Clinical Services Laboratory,Illumina RCV000778608 SCV000914918 pathogenic HADHA-Related Disorders 2018-09-20 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000174836 SCV000967670 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2016-04-27 criteria provided, single submitter clinical testing The p.Glu510Gln variant in HADHA has been reported in >25 individuals with Long- chain 3-hydroxyacyl-CoA dehydrogenase deficiency in the homozygous and compound heterozygous state (Ijlst 1994, Baskin 2010, Olpin 2005) and is the most common cause of LCHAD deficiency (Polinati 2015). This variant has been identified in 0 .168% (112/66738) of European chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs137852769). Although this variant h as been seen in the general population, its frequency is low enough to be consis tent with a recessive carrier frequency. In vitro functional studies provide som e evidence that the p.Glu510Gln variant may impact protein function (Polinati 20 15). In summary, this variant meets criteria to be classified as pathogenic for Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in an autosomal recessive manner based upon genetic and functional evidence. ACMG/AMP Criteria applied: PS 3_Supporting, PM2_Supporting, PM3_Very Strong
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001910 SCV001159663 pathogenic not specified 2018-12-17 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV000174836 SCV001162946 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000174836 SCV001193948 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2019-11-13 criteria provided, single submitter clinical testing NM_000182.4(HADHA):c.1528G>C(E510Q, aka E474Q) is classified as pathogenic in the context of HADHA-related disorders. Sources cited for classification include the following: PMID 7811722, 15902556 and 8770876. Classification of NM_000182.4(HADHA):c.1528G>C(E510Q, aka E474Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000185933 SCV001250298 pathogenic not provided 2018-07-01 criteria provided, single submitter clinical testing
OMIM RCV000009266 SCV000029484 pathogenic Mitochondrial trifunctional protein deficiency 1999-10-01 no assertion criteria provided literature only
OMIM RCV000009267 SCV000029485 pathogenic Lchad deficiency with maternal acute fatty liver of pregnancy 1999-10-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.