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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 31, 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:: RCV000535911.20

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]

Condition(s)

Name:: Mitochondrial trifunctional protein deficiency
Identifiers:: MONDO: MONDO:0012172; MedGen: C1969443; Orphanet: 746; OMIM: PS609015

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
SCV000611201	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 16, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000645773	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 7811722, 8739956, 11773547, 18408953, 19852779, 20583174, 21103935, 21549624, 23868323, 25888220, 26109258, 26653362, 27491397, 8770876, 14630990, 15902556, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000611201

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 16, 2022)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000645773

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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, Wanders RJ, Ushikubo S, Kamijo T, Hashimoto T.

Biochim Biophys Acta. 1994 Dec 8;1215(3):347-50.

PubMed [citation]

PMID:: 7811722

See all PubMed Citations (18)

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV000611201.2

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000645773.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

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.

#	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

Last Updated: Nov 3, 2024

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