rs769580842
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000380649.8(HADHA):βc.1793_1794delβ(p.His598ArgfsTer33) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,312 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. H598H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000380649.8 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HADHA | NM_000182.5 | c.1793_1794del | p.His598ArgfsTer33 | frameshift_variant | 17/20 | ENST00000380649.8 | NP_000173.2 | |
GAREM2 | XM_011532567.4 | c.1683+6353_1683+6354del | intron_variant | XP_011530869.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HADHA | ENST00000380649.8 | c.1793_1794del | p.His598ArgfsTer33 | frameshift_variant | 17/20 | 1 | NM_000182.5 | ENSP00000370023 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251486Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000151 AC: 22AN: 1461752Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727186
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74482
ClinVar
Submissions by phenotype
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 10, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 01, 2022 | PM2, PS3_supporting, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 09, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11855930, 29519241, 31980526, 12442268, 12971428, 31589614, 32778825) - |
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;CN376812:Mitochondrial trifunctional protein deficiency 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 23, 2022 | The homozygous c.1793_1794del, p.(His598ArgfsTer33) variant identified in the HADHA gene is a deletion of two nucleotides in exon# 17 of this 20-exon gene which alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is found with low frequency in population databases gnomADv2.1.1, gnomADv3.1.2, TOPMed Freeze 8 (21 out of 590,312 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in those databases. This variant is reported as Pathogenic / Likely Pathogenic in ClinVar (Variation ID: 188962) and has been reported as homozygous in at least two unrelated infants affected with HADHA-related disorders [PMID: 29519241, 11855930]; a newborn with severe cardiomyopathy at first day of life who died of lactic acidosis at 4 days old [PMID: 29519241], and in another newborn with mitochondrial TFP deficiency [PMID: 11855930]. Given its deleterious nature, low frequency in population databases, and prior observation as homozygous in apparently unrelated affected neonates in the literature, the homozygous c.1793_1794del, p.(His598ArgfsTer33) variant identified in the HADHA gene is reported here as Pathogenic. - |
Mitochondrial trifunctional protein deficiency 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 18, 2024 | - - |
Mitochondrial trifunctional protein deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 17, 2021 | Variant summary: HADHA c.1793_1794delAT (p.His598ArgfsX33) 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 2.8e-05 in 251486 control chromosomes (gnomAD). c.1793_1794delAT has been reported in the literature in individuals affected with Mitochondrial trifunctional protein deficiency (MTFP); in a homozygous patient with maternal uniparental disomy for chromosome 2 (Hintz 2002, Spiekerkoetter 2002) and in two other patients, where one of them was a confirmed homozygote (Lee 2003, Kang 2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on enzyme activity in cultured fibroblasts which revealed marked deficiencies in both LCHAD and LKAT activities, consistent with complete TFP deficiency. Acylcarnitine analysis of a blood spot from the original newborn screening card was also consistent with the established diagnosis (Hintz 2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change creates a premature translational stop signal (p.His598Argfs*33) 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 (rs769580842, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 11855930). This variant is also known as 1793-94delAT, R593ter. ClinVar contains an entry for this variant (Variation ID: 188962). 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