VCV000100085.82 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(27)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 100085 Accession: VCV000100085.82

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.3 2: 26195184 (GRCh38) [ NCBI UCSC ] 2: 26418053 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 28, 2015	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000182.5:c.1528G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000173.2:p.Glu510Gln	missense
NC_000002.12:g.26195184C>G
NC_000002.11:g.26418053C>G
NG_007121.1:g.54437G>C
LRG_747t1:c.1528G>C	LRG_747p1:p.Glu510Gln
	P40939:p.Glu510Gln

... more HGVS ... less HGVS

Protein change

E510Q

Other names

p.E510Q:GAG>CAG

Canonical SPDI

NC_000002.12:26195183:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00071

Exome Aggregation Consortium (ExAC) 0.00120

The Genome Aggregation Database (gnomAD), exomes 0.00123

The Genome Aggregation Database (gnomAD) 0.00182

Links

ClinGen: CA119870 Genetic Testing Registry (GTR): GTR000246713 UniProtKB: P40939#VAR_002273 OMIM: 600890.0001 dbSNP: rs137852769 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GAREM2		-	-	GRCh38 GRCh37	14	576
HADHA		-	-	GRCh38 GRCh37	475	1045

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Mitochondrial trifunctional protein deficiency	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV000009266.19
LCHAD deficiency with maternal acute fatty liver of pregnancy	Pathogenic (1)	no assertion criteria provided	Oct 1, 1999	RCV000009267.14
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Mar 27, 2024	RCV000174836.28
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000185933.49
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Sep 7, 2014	RCV000624767.10
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Mitochondrial trifunctional protein deficiency	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000535911.20
HADHA-related disorder	Pathogenic (2)	criteria provided, single submitter	Sep 20, 2018	RCV000778608.14
not specified	Pathogenic (1)	criteria provided, single submitter	Dec 17, 2018	RCV001001910.15

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 20, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	HADHA-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914918.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (10) PubMed: 9266371‚ 23868323‚ 26024122‚ 25888220‚ 8770876‚ 7811722‚ 15902556‚ 20814823‚ 21549624‚ 23430857 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 02, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695940.2 First in ClinVar: Apr 03, 2017 Last updated: Aug 08, 2020	Publications: PubMed (2) PubMed: 25888220‚ 26109258 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762130.1 First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021	Clinical Features: Rod-cone dystrophy (present) , Abnormal circulating long-chain fatty-acid concentration (present) Sex: female
Pathogenic (Dec 12, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002051516.2 First in ClinVar: Jan 08, 2022 Last updated: Feb 13, 2022	Comment: PM3_Very_Strong, PS3
Pathogenic (Sep 07, 2014)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000740753.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (5) PubMed: 27117294‚ 7811722‚ 25888220‚ 8770876‚ 26024122 Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: Caucasian
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001162946.2 First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250298.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: HADHA: PM3:Very Strong, PM2:Supporting, PP1, PP3, PS3:Supporting Number of individuals with the variant: 6
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Affected status: no Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000538038.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Comment: 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 … (more) 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. (less)
Pathogenic (Nov 07, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	LCHAD deficiency Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000595089.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Pathogenic (Dec 06, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000226211.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 10352164 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HADHA Number of individuals with the variant: 26 Sex: mixed
Pathogenic (Apr 27, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967670.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (4) PubMed: 7811722‚ 20583174‚ 15902556‚ 26024122 Comment: 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 … (more) 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 (less) Number of individuals with the variant: 2
Pathogenic (Nov 13, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193948.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020	Publications: PubMed (3) PubMed: 7811722‚ 15902556‚ 8770876 Comment: 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. … (more) 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. (less)
Pathogenic (Mar 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial trifunctional protein deficiency 1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368518.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PP3.
Pathogenic (Dec 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512752.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting Geographic origin: Brazil
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Mitochondrial trifunctional protein deficiency 1 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516533.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Nov 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713971.3 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Publications: PubMed (1) PubMed: 7811722 Comment: PP3, PS3, PS4 Number of individuals with the variant: 3
Pathogenic (Nov 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024943.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Mitochondrial trifunctional protein deficiency Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000645773.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (17) PubMed: 28492532‚ 7811722‚ 8739956‚ 11773547‚ 14630990‚ 15902556‚ 18408953‚ 19852779‚ 20583174‚ 21103935‚ 21549624‚ 23868323‚ 25888220‚ 26109258‚ 26653362‚ 27491397‚ 8770876 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051808.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Dec 17, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159663.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: 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 … (more) 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. (less)
Pathogenic (Apr 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Centre for Inherited Metabolic Diseases, Karolinska University Hospital Accession: SCV001554478.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Family history: no Secondary finding: no
Pathogenic (Apr 09, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000238888.10 First in ClinVar: Jul 18, 2015 Last updated: Apr 17, 2019	Comment: 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, … (more) 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) (less)
Pathogenic (Mar 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial trifunctional protein deficiency 1 Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611201.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Deficiency of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458398.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Oct 01, 1999)	no assertion criteria provided Method: literature only	LCHAD DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029484.5 First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2023	Publications: PubMed (6) PubMed: 7811722‚ 7846063‚ 8770876‚ 9003853‚ 10518281‚ 23868323 Comment on evidence: Based on numbering from the start codon, which was used by IJlst et al. (1994), this mutation is designated glu510-to-gln (E510Q). Sims et al. (1995) … (more) Based on numbering from the start codon, which was used by IJlst et al. (1994), this mutation is designated glu510-to-gln (E510Q). Sims et al. (1995) had designated the mutation GLU474GLN (E474Q) based on numbering of the mature protein. LCHAD Deficiency with Maternal Acute Fatty Liver of Pregnancy IJlst et al. (1994) identified a 1528G-C transversion in exon 15 of the HADHA gene, resulting in an E510Q substitution, in approximately 87% of the chromosomes in patients with LCHAD deficiency (609016). Sims et al. (1995) used single-strand conformation variance (SSCV) analysis of the alpha subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase to determine the molecular basis of LCHAD deficiency in 3 families in which children presented with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mother had acute fatty liver and associated severe complications during pregnancy. The analysis in 2 affected children demonstrated homozygosity for the E474Q mutation. The third child was compound heterozygous for E474Q and Q342X (600890.0002). IJlst et al. (1996) developed a PCR-RFLP method to identify the E474Q mutation in genomic DNA. Functional expression studies in S. cerevisiae showed that the mutation is directly responsible for the loss of LCHAD activity. Tyni et al. (1997) discussed the clinical presentation of 13 patients with LCHAD deficiency due to a homozygous E474Q mutation. The patients had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Recurrent metabolic crises had occurred in 7 patients; the other 6 had a steadily progressive course. Cholestatic liver disease, which is uncommon in beta-oxidation defects, was found in 2 patients. One patient had peripheral neuropathy, and 6 had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. Radiologically, there was bilateral periventricular or focal cortical lesions in 3 patients and brain atrophy in 1. Only 1 patient, who had dietary treatment for 9 years, was alive at the age of 14 years; all others died before they were 2 years of age. The experience indicated the importance of recognizing the clinical features of LCHAD deficiency for the early institution of dietary management, which can alter the otherwise invariably poor prognosis. Ibdah et al. (1999) reported a patient who presented at 2 months of age with generalized tonic-clonic seizure due to an acute infantile hypocalcemia and vitamin D deficiency. He also had occult, unexplained cholestatic liver disease and impairment of 25-hydroxylation of vitamin D secondary to hepatic steatosis. Sudden unexpected death occurred at 8 months. Molecular analysis revealed homozygosity for the E474Q mutation. The mother had preeclampsia during the third trimester of her pregnancy. Mitochondrial Trifunctional Protein Deficiency 1 In a man with mitochondrial trifunctional protein deficiency (MTPD1; 609015), Liewluck et al. (2013) identified compound heterozygous mutations in the HADHA gene: E510Q and a splice site mutation (600890.0004). The patient presented in his late forties with exercise-induced rhabdomyolysis and was found to have features of a mild sensorimotor axonal peripheral neuropathy affecting the lower limbs. Laboratory studies showed an abnormal acylcarnitine profile, suggesting a defect in HADHA activity, although patient cells were not available for study. (less)
Pathogenic (Oct 01, 1999)	no assertion criteria provided Method: literature only	LCHAD DEFICIENCY WITH MATERNAL ACUTE FATTY LIVER OF PREGNANCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029485.5 First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2023	Publications: PubMed (6) PubMed: 7811722‚ 7846063‚ 8770876‚ 9003853‚ 10518281‚ 23868323 Comment on evidence: Based on numbering from the start codon, which was used by IJlst et al. (1994), this mutation is designated glu510-to-gln (E510Q). Sims et al. (1995) … (more) Based on numbering from the start codon, which was used by IJlst et al. (1994), this mutation is designated glu510-to-gln (E510Q). Sims et al. (1995) had designated the mutation GLU474GLN (E474Q) based on numbering of the mature protein. LCHAD Deficiency with Maternal Acute Fatty Liver of Pregnancy IJlst et al. (1994) identified a 1528G-C transversion in exon 15 of the HADHA gene, resulting in an E510Q substitution, in approximately 87% of the chromosomes in patients with LCHAD deficiency (609016). Sims et al. (1995) used single-strand conformation variance (SSCV) analysis of the alpha subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase to determine the molecular basis of LCHAD deficiency in 3 families in which children presented with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mother had acute fatty liver and associated severe complications during pregnancy. The analysis in 2 affected children demonstrated homozygosity for the E474Q mutation. The third child was compound heterozygous for E474Q and Q342X (600890.0002). IJlst et al. (1996) developed a PCR-RFLP method to identify the E474Q mutation in genomic DNA. Functional expression studies in S. cerevisiae showed that the mutation is directly responsible for the loss of LCHAD activity. Tyni et al. (1997) discussed the clinical presentation of 13 patients with LCHAD deficiency due to a homozygous E474Q mutation. The patients had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Recurrent metabolic crises had occurred in 7 patients; the other 6 had a steadily progressive course. Cholestatic liver disease, which is uncommon in beta-oxidation defects, was found in 2 patients. One patient had peripheral neuropathy, and 6 had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. Radiologically, there was bilateral periventricular or focal cortical lesions in 3 patients and brain atrophy in 1. Only 1 patient, who had dietary treatment for 9 years, was alive at the age of 14 years; all others died before they were 2 years of age. The experience indicated the importance of recognizing the clinical features of LCHAD deficiency for the early institution of dietary management, which can alter the otherwise invariably poor prognosis. Ibdah et al. (1999) reported a patient who presented at 2 months of age with generalized tonic-clonic seizure due to an acute infantile hypocalcemia and vitamin D deficiency. He also had occult, unexplained cholestatic liver disease and impairment of 25-hydroxylation of vitamin D secondary to hepatic steatosis. Sudden unexpected death occurred at 8 months. Molecular analysis revealed homozygosity for the E474Q mutation. The mother had preeclampsia during the third trimester of her pregnancy. Mitochondrial Trifunctional Protein Deficiency 1 In a man with mitochondrial trifunctional protein deficiency (MTPD1; 609015), Liewluck et al. (2013) identified compound heterozygous mutations in the HADHA gene: E510Q and a splice site mutation (600890.0004). The patient presented in his late forties with exercise-induced rhabdomyolysis and was found to have features of a mild sensorimotor axonal peripheral neuropathy affecting the lower limbs. Laboratory studies showed an abnormal acylcarnitine profile, suggesting a defect in HADHA activity, although patient cells were not available for study. (less)
Pathogenic (Sep 18, 2024)	no assertion criteria provided Method: clinical testing	HADHA-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120838.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnosis, Treatment, and Clinical Outcome of Patients with Mitochondrial Trifunctional Protein/Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency.	De Biase I	JIMD reports	2017	PMID: 27117294
Characterization of Chorioretinopathy Associated with Mitochondrial Trifunctional Protein Disorders: Long-Term Follow-up of 21 Cases.	Boese EA	Ophthalmology	2016	PMID: 27491397
Peripheral neuropathy in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency - A follow-up EMG study of 12 patients.	Immonen T	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2016	PMID: 26653362
Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate.	Djouadi F	Journal of inherited metabolic disease	2016	PMID: 26109258
Patient-Specific Induced Pluripotent Stem Cell-Derived RPE Cells: Understanding the Pathogenesis of Retinopathy in Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency.	Polinati PP	Investigative ophthalmology & visual science	2015	PMID: 26024122
Clinical outcome, biochemical and therapeutic follow-up in 14 Austrian patients with Long-Chain 3-Hydroxy Acyl CoA Dehydrogenase Deficiency (LCHADD).	Karall D	Orphanet journal of rare diseases	2015	PMID: 25888220
Mitochondrial trifunctional protein deficiency: a rare cause of adult-onset rhabdomyolysis.	Liewluck T	Muscle & nerve	2013	PMID: 23868323
Prevalence of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency in Estonia.	Joost K	JIMD reports	2012	PMID: 23430857
Comprehensive cDNA study and quantitative analysis of mutant HADHA and HADHB transcripts in a French cohort of 52 patients with mitochondrial trifunctional protein deficiency.	Boutron A	Molecular genetics and metabolism	2011	PMID: 21549624
Urgent metabolic service improves survival in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency detected by symptomatic identification and pilot newborn screening.	Sykut-Cegielska J	Journal of inherited metabolic disease	2011	PMID: 21103935
A comprehensive HADHA c.1528G>C frequency study reveals high prevalence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in Poland.	Piekutowska-Abramczuk D	Journal of inherited metabolic disease	2010	PMID: 20814823
Paternal isodisomy of chromosome 2 as a cause of long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.	Baskin B	American journal of medical genetics. Part A	2010	PMID: 20583174
Next generation sequence analysis for mitochondrial disorders.	Vasta V	Genome medicine	2009	PMID: 19852779
Acute fatty liver of pregnancy and neonatal long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency.	Gutiérrez Junquera C	European journal of pediatrics	2009	PMID: 18408953
Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency.	Olpin SE	Journal of inherited metabolic disease	2005	PMID: 15902556
General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover.	Spiekerkoetter U	Pediatric research	2004	PMID: 14630990
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients.	den Boer ME	Pediatrics	2002	PMID: 11773547
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: variable expressivity of maternal illness during pregnancy and unusual presentation with infantile cholestasis and hypocalcaemia.	Ibdah JA	Journal of inherited metabolic disease	1999	PMID: 10518281
A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women.	Ibdah JA	The New England journal of medicine	1999	PMID: 10352164
Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations.	IJlst L	Journal of inherited metabolic disease	1997	PMID: 9266371
Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: clinical presentation of thirteen patients.	Tyni T	The Journal of pediatrics	1997	PMID: 9003853
Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.	IJlst L	The Journal of clinical investigation	1996	PMID: 8770876
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a new method to identify the G1528C mutation in genomic DNA showing its high frequency (approximately 90%) and identification of a new mutation (T2198C).	Ijlst L	Journal of inherited metabolic disease	1996	PMID: 8739956
The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy.	Sims HF	Proceedings of the National Academy of Sciences of the United States of America	1995	PMID: 7846063
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.	IJlst L	Biochimica et biophysica acta	1994	PMID: 7811722
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HADHA	-	-	-	-
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Text-mined citations for rs137852769 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852769 ...