rs781205883
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000182.5(HADHA):βc.274_278delβ(p.Ser92LysfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,612,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. S92S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000182.5 frameshift
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.274_278del | p.Ser92LysfsTer10 | frameshift_variant | 4/20 | ENST00000380649.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HADHA | ENST00000380649.8 | c.274_278del | p.Ser92LysfsTer10 | frameshift_variant | 4/20 | 1 | NM_000182.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251432Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135884
GnomAD4 exome AF: 0.0000329 AC: 48AN: 1460216Hom.: 0 AF XY: 0.0000330 AC XY: 24AN XY: 726542
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74356
ClinVar
Submissions by phenotype
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2020 | Variant summary: HADHA c.274_278delTCATC (p.Ser92LysfsX10) 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 allele was found at a frequency of 8e-06 in 251432 control chromosomes (gnomAD). c.274_278delTCATC has been reported in a compound heterozygous state and a homozygous state in multiple individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency or Mitochondrial Trifunctional Protein Deficiency (Ibdah_1999, Boutron_2011, Boese_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Dec 23, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Apr 30, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2013 | The c.274_278delTCATC mutation in the HADHA gene has been reported previously in association with long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency using alternate nomenclature (Ibdah et al., 1999). The deletion causes a frameshift starting with codon Serine 92, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Ser92LysfsX10. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in HADHA panel(s). - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 30, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | HADHA: PVS1, PM2, PM3 - |
HADHA-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 25, 2017 | The HADHA c.274_278delTCATC (p.Ser92LysfsTer10) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Ser92LysfsTer10 variant (also referred to as delta271-275 in the literature), has been reported in at least five studies and is found in a total of nine individuals with trifunctional protein (TFP) deficiency or LCHAD deficiency. Specifically, the p.Ser92LysfsTer10 variant was reported in a homozygous state in one infant with severe, neonatal-onset TFP deficiency (Boutron et al. 2011). It has also been reported in a compound heterozygous state in eight individuals with TFP or LCHAD deficiency with varying presentations (Ibdah et al. 1999; Yang et al. 2002; Gillingham et al. 2003; Boutron et al. 2011; Fletcher et al. 2012). Control data are unavailable for this variant which is also not reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of frameshift variants and the evidence from the literature, the p.Ser92LysfsTer10 variant is classified as pathogenic for HADHA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Ser92Lysfs*10) 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 (rs781205883, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency or mitochondrial trifunctional protein deficiency (PMID: 10352164, 12809642, 21549624, 27491397). ClinVar contains an entry for this variant (Variation ID: 189105). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at