rs1243779049
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000182.5(HADHA):c.1195C>T(p.Arg399Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,766 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 Likely 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.1195C>T | p.Arg399Ter | stop_gained | 12/20 | ENST00000380649.8 | |
GAREM2 | XM_011532567.4 | c.*1768G>A | 3_prime_UTR_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HADHA | ENST00000380649.8 | c.1195C>T | p.Arg399Ter | stop_gained | 12/20 | 1 | NM_000182.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461556Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727110
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74358
ClinVar
Submissions by phenotype
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 13, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 10, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 12, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 02, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2023 | Nonsense 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21549624, 33610471, 33638202, 33392894) - |
Mitochondrial trifunctional protein deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change creates a premature translational stop signal (p.Arg399*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 21549624). ClinVar contains an entry for this variant (Variation ID: 449455). 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