Total submissions: 14
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV006456827 | SCV007344043 | pathogenic | PNPT1-related disorder | 2026-01-14 | criteria provided, single submitter | clinical testing | Variant summary: PNPT1 c.1519G>T (p.Ala507Ser) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00021 in 250814 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in PNPT1, allowing no conclusion about variant significance. c.1519G>T has been observed in multiple compound heterozygous individuals affected with PNPT1-Related Disorders (e.g. Slavotinek_2015, Nogueira_2019, Ruis_2019, Dhir_2018). These data indicate that the variant is very likely to 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: 25457163, 30831263, 31752325, 30046113). ClinVar contains an entry for this variant (Variation ID: 215010). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV000680151 | SCV005913413 | pathogenic | Combined oxidative phosphorylation defect type 13 | 2022-04-06 | criteria provided, single submitter | research | |
| Ce |
RCV000197606 | SCV004142195 | likely pathogenic | not provided | 2022-08-01 | criteria provided, single submitter | clinical testing | PNPT1: PP1:Strong, PM2, PM3, PM5:Supporting |
| 3billion | RCV000680151 | SCV004013712 | likely pathogenic | Combined oxidative phosphorylation defect type 13 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.26; 3Cnet: 0.64). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000215010 / PMID: 25457163). A different missense change at the same codon (p.Ala507Gly) has been reported to be associated with PNPT1 related disorder (PMID: 32020600). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. | |
| Baylor Genetics | RCV003152598 | SCV003841196 | pathogenic | Spinocerebellar ataxia type 25 | criteria provided, single submitter | clinical testing | ||
| Baylor Genetics | RCV003147399 | SCV003836298 | pathogenic | Autosomal recessive nonsyndromic hearing loss 70 | 2022-03-08 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000680151 | SCV002767649 | pathogenic | Combined oxidative phosphorylation defect type 13 | 2020-05-21 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine (exon 19). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (60 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (RNase PH C domain; PMID: 31752325) (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple patients with PNPT1-related disorders (ClinVar, PMID: 30046113; 30831263; 25457163; 31752325) (P) 1001 - Strong functional evidence supporting abnormal protein function. Functional studies performed on fibroblast in a compound heterozygous patient showed reduced PNPase expression (PMID: 30046113) (P) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease.* (P) 1206 - Variant is paternally inherited.* (N) *Whole genome TRIO analysis was performed at the Garvan Institute under research settings. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
| Labcorp Genetics |
RCV000197606 | SCV002225526 | pathogenic | not provided | 2025-11-25 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 507 of the PNPT1 protein (p.Ala507Ser). This variant is present in population databases (rs143712760, gnomAD 0.05%). This missense change has been observed in individual(s) with PNPT1-related conditions (PMID: 25326635, 25457163, 30831263, 31752325, 32313153). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 215010). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PNPT1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV001266860 | SCV001445040 | pathogenic | Inborn genetic diseases | 2018-12-19 | criteria provided, single submitter | clinical testing | |
| Kids Research, |
RCV001089488 | SCV001244732 | pathogenic | Combined oxidative phosphorylation defect type 13; Autosomal recessive nonsyndromic hearing loss 70 | criteria provided, single submitter | research | ||
| Rare Disease Group, |
RCV000787360 | SCV000926322 | likely pathogenic | Neurodevelopmental disorder | 2019-04-09 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000197606 | SCV000252111 | likely pathogenic | not provided | 2026-01-27 | criteria provided, single submitter | clinical testing | In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28594066, 26016801, 28645153, 30244537, 30046113, 30831263, 31752325, 25457163, 32313153, 31694722, 33726816, 34440436, 34426522, 35012964, 30029642, 33199448, 36147510, 32020600, 38465286, 25326635, 11080643, 39997218, 41028987) |
| Baylor Genetics | RCV000680151 | SCV000807616 | uncertain significance | Combined oxidative phosphorylation defect type 13 | 2017-09-01 | flagged submission | clinical testing | Likely pathogenicity based on finding it twice in our laboratory in trans with another variant in affacted individuals: a 4-year-old male with global delays, speech articulation disroder, hypotonia; a 6-year-old male with spastic paraplegia, intellectual disability, anosmia, dysphagia, similarly affected sib (who is also compound heterozygous). Heterozygotes would be expected to be asymptomatic carriers. |
| OMIM | RCV000680151 | SCV000257433 | pathogenic | Combined oxidative phosphorylation defect type 13 | 2015-11-01 | no assertion criteria provided | literature only |