Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Wong Mito Lab, |
RCV000502841 | SCV000598178 | likely pathogenic | Mitochondrial DNA depletion syndrome 13 | 2017-08-10 | criteria provided, single submitter | clinical testing | The NM_012160.4:c.1790A>C (NP_036292.2:p.Gln597Pro) [GRCH38: NC_000006.12:g.98874354T>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 13 in multiple affected family members. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. PP4:Patient’s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Pathogenic. |
| Gene |
RCV000657861 | SCV000779621 | likely pathogenic | not provided | 2018-05-23 | criteria provided, single submitter | clinical testing | The Q597P variant has been published in patients who also harbored another variant in the FBXL4 gene with symptoms that include early-onset lactic acidemia, hypotonia, encephalopathy, hyperammonemia, defects in the respiratory chain and mitochondrial DNA depletion (Gai et al. 2013; Morton et al. 2016). The Q597P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Q597P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In summary, we interpret this variant as likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Baylor Genetics | RCV000502841 | SCV000807422 | pathogenic | Mitochondrial DNA depletion syndrome 13 | 2017-09-01 | criteria provided, single submitter | clinical testing | This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant in an 8-year-old female with regression, basal ganglia abnormalities, absent speech, autistic features, hypotonia, spasticity, exercise intolerance, ataxia, severe renal tubular acidosis, scoliosis, primary mitochondrial respiratory chain disease |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004525949 | SCV005040021 | uncertain significance | not specified | 2024-03-08 | criteria provided, single submitter | clinical testing | Variant summary: FBXL4 c.1790A>C (p.Gln597Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250346 control chromosomes (gnomAD). c.1790A>C has been reported in the literature in individuals affected with Leigh Syndrome and Mitochondrial disorder (examples: Gai_2013, Morton_2016, Ballout_2019, Alves_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32445240, 30804983, 23993194, 34052969, 27858371). ClinVar contains an entry for this variant (Variation ID: 437486). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Mayo Clinic Laboratories, |
RCV000657861 | SCV000802749 | uncertain significance | not provided | 2016-03-08 | no assertion criteria provided | clinical testing |