Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001378129 | SCV001575629 | likely pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-04-09 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the SDHA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant has not been reported in the literature in individuals affected with SDHA-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts a region of the SDHA protein in which other variant(s) (p.Arg31Gln) have been observed in individuals with SDHA-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of skipping of exon 2, but is expected to preserve the integrity of the reading-frame (Invitae). ClinVar contains an entry for this variant (Variation ID: 1066987). |
| Ambry Genetics | RCV003169937 | SCV003904319 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-08 | criteria provided, single submitter | clinical testing | The c.150+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 2 of the SDHA gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is insufficient (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |