Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Fulgent Genetics, |
RCV000001260 | SCV002788285 | likely pathogenic | Coenzyme Q10 deficiency, primary, 3 | 2022-05-18 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002509141 | SCV002819920 | uncertain significance | not specified | 2022-12-30 | criteria provided, single submitter | clinical testing | Variant summary: PDSS2 c.1145C>T (p.Ser382Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251440 control chromosomes (gnomAD). c.1145C>T has been reported in the literature in a compound heterozygous individual, who carried a nonsense variant in trans, and was affected with Coenzyme Q10 Deficiency, Primary, 3 (Lopez_2006), and in a homozygous individual affected with Steroid Resistant Nephrotic syndrome, a related disorder (Sadowski_2015). These data indicate that the variant may be associated with disease. Publications also reported experimental evidence on patient derived fibroblasts (reported in Lopez_2006), demonstrating severely decreased CoQ10 levels and markedly reduced ATP synthesis (Lopez_2006, Quinzii_2008), and both the low CoQ10 levels and bioenergetic abnormalities could be corrected in vitro with COQ10 administration after one week of treatment (Lopez_2010), confirming a causal role for the PDSS2 gene in this patient. On the other hand, to our knowledge only a few variants have been reported in additional affected individuals, with limited biochemical phenotype details (PMIDs 25349199, 29032433), therefore current evidence is not sufficient to clearly establish whether loss-of-function variant can cause disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Invitae | RCV002512637 | SCV003439502 | uncertain significance | not provided | 2022-01-31 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 382 of the PDSS2 protein (p.Ser382Leu). This variant is present in population databases (rs118203956, gnomAD 0.006%). This missense change has been observed in individuals with PDSS2-related conditions (PMID: 17186472, 29127259). ClinVar contains an entry for this variant (Variation ID: 1201). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| OMIM | RCV000001260 | SCV000021410 | pathogenic | Coenzyme Q10 deficiency, primary, 3 | 2006-12-01 | no assertion criteria provided | literature only | |
| Gene |
RCV000001260 | SCV000494147 | not provided | Coenzyme Q10 deficiency, primary, 3 | no assertion provided | literature only | ||
| Yale Center for Mendelian Genomics, |
RCV001849250 | SCV002107040 | likely pathogenic | Nephrotic syndrome | 2017-11-10 | no assertion criteria provided | literature only |