NM_000182.5(HADHA):c.1528G>C (p.Glu510Gln) AND Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Mar 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000174836.28

Allele description [Variation Report for NM_000182.5(HADHA):c.1528G>C (p.Glu510Gln)]

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

Genes:

GAREM2:GRB2 associated regulator of MAPK1 subtype 2 [Gene - OMIM - HGNC]
HADHA:hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

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

Other names:

p.E510Q:GAG>CAG

HGVS:

NC_000002.12:g.26195184C>G
NG_007121.1:g.54437G>C
NM_000182.5:c.1528G>CMANE SELECT
NP_000173.2:p.Glu510Gln
LRG_747t1:c.1528G>C
LRG_747p1:p.Glu510Gln
NC_000002.11:g.26418053C>G
NM_000182.4:c.1528G>C
P40939:p.Glu510Gln

Protein change:

E510Q; GLU510GLN

Links:

UniProtKB: P40939#VAR_002273; OMIM: 600890.0001; dbSNP: rs137852769

NCBI 1000 Genomes Browser:

rs137852769

Molecular consequence:

NM_000182.5:c.1528G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Synonyms:: Deficiency of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase; LCHAD Deficiency
Identifiers:: MONDO: MONDO:0012173; MedGen: C3711645; Orphanet: 5; OMIM: 609016

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000538038	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000595089	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000695940	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 2, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25888220, 26109258 Citation Link,
SCV000967670	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Apr 27, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7811722, 20583174, 15902556, 26024122, 24033266
SCV001162946	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193948	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Nov 13, 2019)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7811722, 15902556, 8770876 Citation Link,
SCV001458398	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001554478	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002512752	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 28, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005051808	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical outcome, biochemical and therapeutic follow-up in 14 Austrian patients with Long-Chain 3-Hydroxy Acyl CoA Dehydrogenase Deficiency (LCHADD).

Karall D, Brunner-Krainz M, Kogelnig K, Konstantopoulou V, Maier EM, Möslinger D, Plecko B, Sperl W, Volkmar B, Scholl-Bürgi S.

Orphanet J Rare Dis. 2015 Feb 22;10:21. doi: 10.1186/s13023-015-0236-7.

PubMed [citation]

PMID:: 25888220
PMCID:: PMC4407779

Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate.

Djouadi F, Habarou F, Le Bachelier C, Ferdinandusse S, Schlemmer D, Benoist JF, Boutron A, Andresen BS, Visser G, de Lonlay P, Olpin S, Fukao T, Yamaguchi S, Strauss AW, Wanders RJ, Bastin J.

J Inherit Metab Dis. 2016 Jan;39(1):47-58. doi: 10.1007/s10545-015-9871-3. Epub 2015 Jun 25.

PubMed [citation]

PMID:: 26109258

See all PubMed Citations (9)

Details of each submission

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538038.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000595089.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695940.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967670.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From Baylor Genetics, SCV001162946.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193948.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001458398.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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

From Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SCV001554478.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	no	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	discovery		1	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512752.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051808.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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