NM_000182.5(HADHA):c.1644del (p.Arg549fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 30, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000807451.6

Allele description [Variation Report for NM_000182.5(HADHA):c.1644del (p.Arg549fs)]

NM_000182.5(HADHA):c.1644del (p.Arg549fs)

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:

Deletion

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_000182.5(HADHA):c.1644del (p.Arg549fs)

HGVS:

NC_000002.12:g.26194616del
NG_007121.1:g.55006del
NM_000182.5:c.1644delMANE SELECT
NP_000173.2:p.Arg549fs
LRG_747t1:c.1644del
LRG_747p1:p.Arg549fs
NC_000002.11:g.26417484del
NC_000002.11:g.26417485del
NM_000182.5:c.1644del

Protein change:

R549fs

Links:

dbSNP: rs1267615713

NCBI 1000 Genomes Browser:

rs1267615713

Molecular consequence:

NM_000182.5:c.1644del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000947504	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 30, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7738175, 21103935, 21549624, 22459206, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000947504

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 30, 2023)

germline

clinical testing

PubMed (5)
[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

Citations

PubMed

Two alpha subunit donor splice site mutations cause human trifunctional protein deficiency.

Brackett JC, Sims HF, Rinaldo P, Shapiro S, Powell CK, Bennett MJ, Strauss AW.

J Clin Invest. 1995 May;95(5):2076-82.

PubMed [citation]

PMID:: 7738175
PMCID:: PMC295799

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, Gradowska W, Piekutowska-Abramczuk D, Andresen BS, Olsen RK, Ołtarzewski M, Pronicki M, Pajdowska M, Bogdańska A, Jabłońska E, Radomyska B, Kuśmierska K, Krajewska-Walasek M, Gregersen N, Pronicka E.

J Inherit Metab Dis. 2011 Feb;34(1):185-95. doi: 10.1007/s10545-010-9244-x. Epub 2010 Nov 20.

PubMed [citation]

PMID:: 21103935

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000947504.6

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 651987). This variant has not been reported in the literature in individuals affected with HADHA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg549Glyfs*6) in the HADHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206).

#	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: Mar 5, 2024

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