Submissions for variant NM_033109.5(PNPT1):c.1519G>T (p.Ala507Ser)

gnomAD frequency: 0.00026  dbSNP: rs143712760

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197606	SCV000252111	likely pathogenic	not provided	2023-07-31	criteria provided, single submitter	clinical testing	In silico analysis supports 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)
Baylor Genetics	RCV000680151	SCV000807616	uncertain significance	Combined oxidative phosphorylation defect type 13	2017-09-01	criteria provided, single submitter	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.
Rare Disease Group, Clinical Genetics, Karolinska Institutet	RCV000787360	SCV000926322	likely pathogenic	Neurodevelopmental disorder	2019-04-09	criteria provided, single submitter	clinical testing
Kids Research, The Children's Hospital at Westmead	RCV001089488	SCV001244732	pathogenic	Combined oxidative phosphorylation defect type 13; Autosomal recessive nonsyndromic hearing loss 70		criteria provided, single submitter	research
Ambry Genetics	RCV001266860	SCV001445040	pathogenic	Inborn genetic diseases	2018-12-19	criteria provided, single submitter	clinical testing
Invitae	RCV000197606	SCV002225526	pathogenic	not provided	2024-01-28	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). 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 not expected to disrupt PNPT1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	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
Baylor Genetics	RCV003147399	SCV003836298	pathogenic	Autosomal recessive nonsyndromic hearing loss 70	2022-03-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003152598	SCV003841196	pathogenic	Spinocerebellar ataxia type 25		criteria provided, single submitter	clinical testing
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.
CeGaT Center for Human Genetics Tuebingen	RCV000197606	SCV004142195	likely pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	PNPT1: PP1:Strong, PM2, PM3, PM5:Supporting
OMIM	RCV000680151	SCV000257433	pathogenic	Combined oxidative phosphorylation defect type 13	2015-11-01	no assertion criteria provided	literature only