ClinVar Miner

Submissions for variant NM_021830.5(TWNK):c.908G>A (p.Arg303Gln)

gnomAD frequency: 0.00001  dbSNP: rs137852956
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV001289123 SCV001476734 uncertain significance not provided 2019-11-13 criteria provided, single submitter clinical testing
Invitae RCV001289123 SCV003441547 pathogenic not provided 2022-11-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg303 amino acid residue in TWNK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707443, 19428252, 20659899). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TWNK protein function. ClinVar contains an entry for this variant (Variation ID: 4628). This missense change has been observed in individual(s) with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PMID: 19353676, 20479361). This variant has been reported in individual(s) with autosomal recessive mitochondrial DNA depletion syndrome (PMID: 31271879); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs137852956, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 303 of the TWNK protein (p.Arg303Gln).
OMIM RCV000004891 SCV000025067 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 2009-05-01 no assertion criteria provided literature only

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