NM_000182.5(HADHA):c.1195C>T (p.Arg399Ter) AND Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jan 13, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000667154.2

Allele description [Variation Report for NM_000182.5(HADHA):c.1195C>T (p.Arg399Ter)]

NM_000182.5(HADHA):c.1195C>T (p.Arg399Ter)

Gene:
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.1195C>T (p.Arg399Ter)
HGVS:
  • NC_000002.12:g.26204087G>A
  • NG_007121.1:g.45534C>T
  • NM_000182.5:c.1195C>TMANE SELECT
  • NP_000173.2:p.Arg399Ter
  • LRG_747t1:c.1195C>T
  • LRG_747p1:p.Arg399Ter
  • NC_000002.11:g.26426956G>A
  • NM_000182.4:c.1195C>T
Protein change:
R399*
Links:
dbSNP: rs1243779049
NCBI 1000 Genomes Browser:
rs1243779049
Molecular consequence:
  • NM_000182.5:c.1195C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000791561Counsylcriteria provided, single submitter
Likely pathogenic
(May 12, 2017)
unknownclinical testing

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

Citation Link,

SCV001337807Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 13, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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, Acquaviva C, Vianey-Saban C, de Lonlay P, de Baulny HO, Guffon N, Dobbelaere D, Feillet F, Labarthe F, Lamireau D, Cano A, de Villemeur TB, Munnich A, Saudubray JM, Rabier D, Rigal O, Brivet M.

Mol Genet Metab. 2011 Aug;103(4):341-8. doi: 10.1016/j.ymgme.2011.04.006. Epub 2011 Apr 19.

PubMed [citation]
PMID:
21549624

Details of each submission

From Counsyl, SCV000791561.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001337807.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: HADHA c.1195C>T (p.Arg399X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251486 control chromosomes. c.1195C>T has been reported in the literature in at-least one individual affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency who displayed MTP (Mitochondrial Trifunctional Protein) deficiency with a late infantile hepatic phenotype (Boutron_2011). These data support the notion that this variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although haploinsufficiency has been reported as a major pathomechanism in MTP deficiency (Boutron_2011). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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