NM_000182.5(HADHA):c.1990_1993dup (p.Ser665Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 16, 2024
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:: RCV001381333.5

Allele description [Variation Report for NM_000182.5(HADHA):c.1990_1993dup (p.Ser665Ter)]

NM_000182.5(HADHA):c.1990_1993dup (p.Ser665Ter)

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:

Duplication

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_000182.5(HADHA):c.1990_1993dup (p.Ser665Ter)

HGVS:

NC_000002.12:g.26192318_26192321dup
NG_007121.2:g.57302_57305dup
NM_000182.5:c.1990_1993dupMANE SELECT
NP_000173.2:p.Ser665Ter
LRG_747t1:c.1990_1993dup
LRG_747:g.57302_57305dup
LRG_747p1:p.Ser665Ter
NC_000002.11:g.26415185_26415186insACTT
NC_000002.11:g.26415187_26415190dup
NG_007121.1:g.57301_57304dup

Protein change:

S665*

Links:

dbSNP: rs757671025

NCBI 1000 Genomes Browser:

rs757671025

Molecular consequence:

NM_000182.5:c.1990_1993dup - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001579659	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	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

SCV001579659

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2024)

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001579659.4

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

Description

This sequence change creates a premature translational stop signal (p.Ser665*) 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). This variant is present in population databases (rs757671025, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with HADHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1069465). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: Sep 29, 2024

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