Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000634895 | SCV000756262 | pathogenic | Multiple acyl-CoA dehydrogenase deficiency | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 12 of the ETFDH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Multiple Acyl-CoA dehydrogenase deficiency (PMID: 7757062). ClinVar contains an entry for this variant (Variation ID: 529451). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects ETFDH function (PMID: 7757062). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 7757062). This variant disrupts the p.Pro534 amino acid residue in ETFDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18289905, 21088898, 22664151; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000634895 | SCV003929369 | pathogenic | Multiple acyl-CoA dehydrogenase deficiency | 2023-04-24 | criteria provided, single submitter | clinical testing | Variant summary: ETFDH c.1690+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site, with additional functional studies suggesting the variant results in skipping of exon 12 in the 4Fe-4S ferredoxin-type, iron-sulphur binding domain (example: Beard_1995). The variant was absent in 249914 control chromosomes. c.1690+1G>T has been reported in the literature in compound heterozygous individuals affected with Glutaric Aciduria, Type 2c (examples: Beard_1995, Goodman_2002). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Beard_1995). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000634895 | SCV004194819 | pathogenic | Multiple acyl-CoA dehydrogenase deficiency | 2023-07-16 | criteria provided, single submitter | clinical testing |