Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002552090 | SCV003448409 | pathogenic | not provided | 2022-10-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 29440775). Experimental studies have shown that this variant affects QRSL1 function (PMID: 29440775). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 834719). This variant has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 29440775). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change falls in intron 7 of the QRSL1 gene. It does not directly change the encoded amino acid sequence of the QRSL1 protein. It affects a nucleotide within the consensus splice site. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001035458 | SCV004099818 | pathogenic | Combined oxidative phosphorylation deficiency 40 | 2023-09-13 | criteria provided, single submitter | clinical testing | Variant summary: QRSL1 c.850-3A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing, leading to a 60% reduction in the amount of wild-type cDNA and the production of two alternative transcripts with premature termination codons (e.g., Kamps_2018). The variant allele was found at a frequency of 8.3e-06 in 239564 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.850-3A>G has been reported in the literature in two homozygous siblings affected with Combined Oxidative Phosphorylation Deficiency 40 (e.g., Kamps_2018), and the variant was shown to segregate with disease among related individuals. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant resulted in approximately 30%-50% of normal OXPHOS activity (e.g., Kamps_2018). The following publication was ascertained in the context of this evaluation (PMID: 29440775). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV001035458 | SCV001198785 | pathogenic | Combined oxidative phosphorylation deficiency 40 | 2020-04-11 | no assertion criteria provided | literature only |