Submissions for variant NM_033109.5(PNPT1):c.1361C>G (p.Ala454Gly)

gnomAD frequency: 0.00001  dbSNP: rs200088200

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000663406	SCV000786694	likely pathogenic	Combined oxidative phosphorylation defect type 13		criteria provided, single submitter	research	The heterozygous p.Ala454Gly 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.Ala454Gly variant has not been reported in the literature, but it has been identified to have a MAF of 0.02% (1/6437) by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200088200). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The Alanine (Ala) at position 454 is highly conserved in mammals and evolutionary distant species, raising the possibility/supporting that a change at this position may not be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001371700	SCV001568274	uncertain significance	not provided	2022-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 454 of the PNPT1 protein (p.Ala454Gly). This variant is present in population databases (rs200088200, gnomAD 0.003%). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 31752325). ClinVar contains an entry for this variant (Variation ID: 548987). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx	RCV001371700	SCV001820223	uncertain significance	not provided	2020-08-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31752325, 23084291, 27759031)