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

gnomAD frequency: 0.00182  dbSNP: rs137852769

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000185933	SCV000226211	pathogenic	not provided	2016-12-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000185933	SCV000238888	pathogenic	not provided	2020-04-09	criteria provided, single submitter	clinical testing	Functional studies found E510Q is associated with no detectable LCHAD enzyme activity (IJlst et al. 1996); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 19852779, 15902556, 25888220, 27117294, 28798025, 30029694, 8770876, 20583174, 25087612, 7846063, 10518281, 21549624, 26109258, 7811722, 26024122, 27491397, 23868323, 26653362, 26676313, 28245050, 29095929, 28559085, 27334895, 31025818, 31479012, 31980526, 32827528, 31589614, 33107778, 33204595)
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	RCV000174836	SCV000595089	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase 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	2022-03-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535911	SCV000645773	pathogenic	Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 510 of the HADHA protein (p.Glu510Gln). This variant is present in population databases (rs137852769, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, or mitochondrial trifunctional protein deficiency (PMID: 7811722, 8739956, 11773547, 14630990, 15902556, 18408953, 19852779, 20583174, 21103935, 21549624, 23868323, 25888220, 26109258, 26653362, 27491397). This variant is also known as p.Glu474Gln or p.E474Q. ClinVar contains an entry for this variant (Variation ID: 100085). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HADHA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HADHA function (PMID: 8770876, 14630990, 15902556). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000174836	SCV000695940	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2020-07-02	criteria provided, single submitter	clinical testing	Variant summary: HADHA c.1528G>C (p.Glu510Gln) results in a conservative amino acid change located in the 3-hydroxyacyl-CoA dehydrogenase, NAD binding domain (IPR006176) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251462 control chromosomes (gnomAD). c.1528G>C has been reported in the literature in several homozygous and compound heterozygous individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency, and is a commonly known pathogenic variant. Publications also reported experimental evidence evaluating an impact on protein function, showing that in homozygous patient derived fibroblasts this variant results in <10% of normal LCHAD activity. Eleven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000624767	SCV000740753	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778608	SCV000914918	pathogenic	HADHA-related disorder	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, Mass General Brigham 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	2024-03-27	criteria provided, single submitter	clinical testing
Myriad Genetics, 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 Center for Human Genetics Tuebingen	RCV000185933	SCV001250298	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	HADHA: PM3:Very Strong, PM2:Supporting, PP1, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000009266	SCV001368518	pathogenic	Mitochondrial trifunctional protein deficiency	2020-03-20	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PP3.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000174836	SCV001554478	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2021-04-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000185933	SCV001713971	pathogenic	not provided	2022-11-16	criteria provided, single submitter	clinical testing	PP3, PS3, PS4
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000185933	SCV001762130	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000185933	SCV002024943	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000185933	SCV002051516	pathogenic	not provided	2020-12-12	criteria provided, single submitter	clinical testing	PM3_Very_Strong, PS3
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000174836	SCV002512752	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2021-12-28	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Mendelics	RCV000009266	SCV002516533	pathogenic	Mitochondrial trifunctional protein deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000174836	SCV005051808	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2024-02-01	criteria provided, single submitter	curation
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
Natera, Inc.	RCV000174836	SCV001458398	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000778608	SCV004120838	pathogenic	HADHA-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The HADHA c.1528G>C variant is predicted to result in the amino acid substitution p.Glu510Gln. This variant has been reported as a recurrent cause of autosomal recessive long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency/mitochondrial trifunctional protein deficiency (Boutron et al. 2011. PubMed ID: 21549624; Karall et al. 2015. PubMed ID: 25888220; Boese et al. 2016. PubMed ID: 27491397). It has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/100085). This variant is reported in 0.39% of alleles in individuals of European (Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic.