Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000185934 | SCV000228808 | pathogenic | not provided | 2014-10-13 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000185934 | SCV000238890 | pathogenic | not provided | 2016-07-01 | criteria provided, single submitter | clinical testing | The c.180+3 A>G splice site variant in the HADHA gene has been previously reported in association with mitochondrial trifunctional protein deficiency (Brackett et al., 1995). This variant reduces the quality of the splice donor site in intron 3, and is expected to cause abnormal gene splicing. |
Fulgent Genetics, |
RCV000763079 | SCV000893602 | pathogenic | Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency | 2021-09-29 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000763079 | SCV000945227 | pathogenic | Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 3 of the HADHA gene. It does not directly change the encoded amino acid sequence of the HADHA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs781222705, gnomAD 0.01%). This variant has been observed in individual(s) with mitochondrial trifunctional protein deficiency or long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (PMID: 7738175, 23868323, 26109258, 27491397). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8731). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3 and introduces a premature termination codon (PMID: 7738175). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000984272 | SCV001426898 | pathogenic | Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency | 2020-07-02 | criteria provided, single submitter | clinical testing | Variant summary: HADHA c.180+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions demonstrating the variant causes skipping of exon 3 resulting in premature stop codon (Brackett_1995). The variant allele was found at a frequency of 5.2e-05 in 251376 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HADHA causing Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (5.2e-05 vs 0.0019), allowing no conclusion about variant significance. c.180+3A>G has been reported in the literature in individuals affected with Mitochondrial Trifunctional Protein Deficiency and Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (e.g. Brackett_1995, Boese_2016, Djouadi_2016, Liewluck_2013). These data indicate that the variant is likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Revvity Omics, |
RCV000185934 | SCV002023446 | likely pathogenic | not provided | 2022-07-08 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000984272 | SCV004191753 | pathogenic | Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency | 2023-10-10 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000009270 | SCV000029488 | pathogenic | Mitochondrial trifunctional protein deficiency | 1995-05-01 | no assertion criteria provided | literature only | |
Counsyl | RCV000984272 | SCV001132411 | likely pathogenic | Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency | 2015-09-11 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000984272 | SCV001462522 | pathogenic | Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency | 2020-09-16 | no assertion criteria provided | clinical testing |