ClinVar Miner

Submissions for variant NM_033109.5(PNPT1):c.1592C>G (p.Thr531Arg)

gnomAD frequency: 0.00008  dbSNP: rs374698153
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191120 SCV000245526 likely pathogenic Combined oxidative phosphorylation defect type 13 2015-02-23 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it three times in our laboratory in trans with another variant in affacted individuals: a 4-year-old male[with A507S] with global delays, speech articulation disorder, hypotonia; a 6-year-old male [with A507S] with spastic paraplegia, intellectual disability, anosmia, dysphagia, similarly affected sib (who is also compound heterozygous); an 18-year-old male [with V509I] with profound intellectual disability, severe bilateral hearing loss, hypotonia, dysmorphisms, short stature, microcephaly, hyperextensibility, myopia, cataract, congenital heart disease, fused kidneys, small testicles, type II diabetes, immunodeficiency (healthy sib NOT compound heterozygous)
GeneDx RCV001705075 SCV000491104 uncertain significance not provided 2023-04-21 criteria provided, single submitter clinical testing Observed in the heterozygous state in a patient with global developmental delay, intellectual disability, feeding difficulties, irritability, microcephaly, and dystonia who also harbored a second PNPT1 gene variant; the phase of the variants is unknown (Rius et al., 2019); Observed in trans with variant of uncertain significance in the PNPT1 gene in an individual with encephalopathy, developmental delay, and hearing loss (Pennisi A et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31752325, 33199448, 36147510, 34740920)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000191120 SCV000786693 likely pathogenic Combined oxidative phosphorylation defect type 13 criteria provided, single submitter research The heterozygous p.Thr531Arg variant in PNPT1 has been identified in the compound heterozygous state by our project in one individual with Combined Oxidative Phosphorylation Deficiency (COPD). The p.Thr531Arg variant has not been reported in the literature, but it has been reported in ClinVar (Variant ID: 209184). Baylor Laboratory reported this variant in 3 probands, however only 1/3 fit the current known clinical spectrum for PNPT1. Functional evidence (PNPase Western Blot, spectrophotometric enzyme assays, Dipstick assays, OXPHOS western blot) supports a pathogenic role for this variant and is consistent with other pathogenic variants (7 publications to date). The spectrophotometric enzyme assays conducted on fibroblasts were normal, which has been observed in other PNPT1- related cases including the one published in EJHG (Alodaib, A., et al. 2016) and others (Vedrenne, V., et al. 2012, Sato, R., et al. 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.
Invitae RCV001705075 SCV002229531 pathogenic not provided 2023-05-20 criteria provided, single submitter clinical testing This variant is present in population databases (rs374698153, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 531 of the PNPT1 protein (p.Thr531Arg). This missense change has been observed in individuals with combined oxidative phosphorylation deficiency (PMID: 31752325, 33199448; external communication). For these reasons, this variant has been classified as Pathogenic. 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 PNPT1 protein function. ClinVar contains an entry for this variant (Variation ID: 209184).
Ambry Genetics RCV002517033 SCV003659941 uncertain significance Inborn genetic diseases 2022-07-17 criteria provided, single submitter clinical testing The c.1592C>G (p.T531R) alteration is located in exon 19 (coding exon 19) of the PNPT1 gene. This alteration results from a C to G substitution at nucleotide position 1592, causing the threonine (T) at amino acid position 531 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV001705075 SCV003809127 uncertain significance not provided 2021-02-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147393 SCV003836361 likely pathogenic Autosomal recessive nonsyndromic hearing loss 70 2022-03-08 criteria provided, single submitter clinical testing

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