rs749848370
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000182.5(HADHA):βc.1981_1999delβ(p.Leu661SerfsTer12) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L661L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000029 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HADHA
NM_000182.5 frameshift, splice_region
NM_000182.5 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.36
Genes affected
HADHA (HGNC:4801): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-26192310-ACTTCAGACTTAGGAGGCAG-A is Pathogenic according to our data. Variant chr2-26192310-ACTTCAGACTTAGGAGGCAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HADHA | NM_000182.5 | c.1981_1999del | p.Leu661SerfsTer12 | frameshift_variant, splice_region_variant | 18/20 | ENST00000380649.8 | |
GAREM2 | XM_011532567.4 | c.1683+5005_1683+5023del | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HADHA | ENST00000380649.8 | c.1981_1999del | p.Leu661SerfsTer12 | frameshift_variant, splice_region_variant | 18/20 | 1 | NM_000182.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135902
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000293 AC: 4AN: 1363324Hom.: 0 AF XY: 0.00000146 AC XY: 1AN XY: 683880
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Dec 11, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 08, 2023 | - - |
Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change creates a premature translational stop signal (p.Leu661Serfs*12) 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 (rs749848370, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with HADHA-related conditions (PMID: 21549624, 32827528). ClinVar contains an entry for this variant (Variation ID: 189089). For these reasons, this variant has been classified as Pathogenic. - |
Mitochondrial trifunctional protein deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 31, 2019 | Variant summary: HADHA c.1981_1999del19 (p.Leu661SerfsX12) 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 reported in patients (HGMD). This exonic variant is located close to a canonical splice-site and therefore could affect mRNA splicing: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251460 control chromosomes. c.1981_1999del19 has been reported in the literature in a compound heterozygous individual affected with Mitochondrial trifunctional protein deficiency (Boutron_2011). This publication reported that the patient carried this variant had 39% of normal LCHAD activity measured from muscle tissue (Boutron_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at