ClinVar Miner

Submissions for variant NM_032620.4(GTPBP3):c.521G>C (p.Arg174Pro)

dbSNP: rs766510741
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetics and Molecular Pathology, SA Pathology RCV002272674 SCV002556665 likely pathogenic Combined oxidative phosphorylation defect type 23 2021-08-02 criteria provided, single submitter clinical testing The GTPBP3 c.521G>C variant is classified as LIKELY PATHOGENIC (PS3, PM2, PP3, PM3_supporting) The GTPBP3 c.521G>C variant is a single nucleotide change in exon 4/9 of the GTPBP3 gene, which is predicted to change the amino acid arginine at position 174 to proline. This variant is located in in the MnmE helical domain (PF12631), which has not been functionally validated. However, other reported variants at positions, p.159 and p.162 located within the MnmE domain, showed structural instability to the dimeric helical structure when mutated in vitro (PMID: 33619562). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs766510741). This variant has not been reported in ClinVar or HGMD. Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has not been described in literature to date. This variant is inherited from both parents, each unaffected parent carries the variant in heterozygosity and no evidence of consanguinity (PM3_supporting). Respiratory chain enzyme studies in skeletal muscle demonstrated Complex I and Complex IV deficiencies, with normal activities of Complex II and Citrate Synthase. These results are consistent with those found in other patients with pathogenic GTPBP3 variants, although not specific for GTPBP3 defects (PS3).

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