2-26194581-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000182.5(HADHA):c.1678C>T(p.Arg560Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,453,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000182.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HADHA | NM_000182.5 | c.1678C>T | p.Arg560Ter | stop_gained | 16/20 | ENST00000380649.8 | |
GAREM2 | XM_011532567.4 | c.1683+7266G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HADHA | ENST00000380649.8 | c.1678C>T | p.Arg560Ter | stop_gained | 16/20 | 1 | NM_000182.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251462Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135904
GnomAD4 exome AF: 0.0000227 AC: 33AN: 1453704Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 14AN XY: 723774
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PVS1, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 29, 2020 | - - |
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 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 8732). This premature translational stop signal has been observed in individuals with mitochondrial trifunctional protein deficiency (PMID: 8865274, 27491397). This variant is present in population databases (rs137852771, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg560*) 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). - |
Mitochondrial trifunctional protein deficiency 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1996 | - - |
Mitochondrial trifunctional protein deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 14, 2019 | Variant summary: HADHA c.1678C>T (p.Arg560X) 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. The variant allele was found at a frequency of 2e-05 in 246244 control chromosomes (gnomAD). c.1678C>T has been reported in the literature in homozygote and compound heterozygote individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (Boutron_2011, Boese_2016). The homozygote patient was found at a have a tritiated-palmitate levels of 13% and 3H-Pal/3H-Myr: normalized ratio between [9,10-3H]-palmitate and [9,10-3H]-myristate detritiation (both results expressed as percentages of the controls mean) of 0.6. This ratio is >0.85 in controls and other long chain fatty acid oxidation defects. 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 pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at