Submissions for variant NM_033109.5(PNPT1):c.1525G>A (p.Val509Ile)

gnomAD frequency: 0.00109  dbSNP: rs146571352

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766604	SCV000252116	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	Observed with a second variant in PNPT1 in a patient with mitochondrial encephalopathy in published literature (PMID: 33199448); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26633545, 34498404, 33199448)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000196452	SCV000297349	uncertain significance	not specified	2015-10-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766604	SCV001152311	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	PNPT1: BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766604	SCV002337156	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000196452	SCV002519149	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002514095	SCV003553949	uncertain significance	Inborn genetic diseases	2021-12-02	criteria provided, single submitter	clinical testing	The c.1525G>A (p.V509I) alteration is located in exon 19 (coding exon 19) of the PNPT1 gene. This alteration results from a G to A substitution at nucleotide position 1525, causing the valine (V) at amino acid position 509 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003152596	SCV003841197	uncertain significance	Spinocerebellar ataxia type 25		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196452	SCV004241732	benign	not specified	2023-12-27	criteria provided, single submitter	clinical testing	Variant summary: PNPT1 c.1525G>A (p.Val509Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 1608332 control chromosomes in the gnomAD database, including 12 homozygotes, strongly suggesting the variant is a benign polymorphism. c.1525G>A has been reported in the literature in an individual affected with mild and chronic encephalopathy and deafness (Pennisi_2022). However, this report does not provide unequivocal conclusions about association of the variant with PNPT1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33199448). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as uncertain significance and two classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Baylor Genetics	RCV000191121	SCV000245527	likely pathogenic	Combined oxidative phosphorylation defect type 13	2014-02-05	flagged submission	clinical testing	Likely pathogenicity based on finding it once in our laboratory in trans with another variant [T531R] in an 18-year-old male 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). Variant likely pathogenic in recessive state; heterozygotes would be carriers.
GenomeConnect, ClinGen	RCV000845061	SCV000986902	not provided	Combined oxidative phosphorylation defect type 13; Autosomal recessive nonsyndromic hearing loss 70		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
PreventionGenetics, part of Exact Sciences	RCV004725040	SCV005335427	uncertain significance	PNPT1-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The PNPT1 c.1525G>A variant is predicted to result in the amino acid substitution p.Val509Ile. This variant was reported in the compound heterozygous state in an individual with mitochondrial disease of variable severity. Specifically, the patient presented with respiratory anomalies, elevated bilirubin, encephalopathy, hypotonia, and cardiac anomalies (Table 1, Patient 1, Pennisi et al 2022. PubMed ID: 33199448). This variant is reported in 0.17% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 12 homozygotes in the gnomADv4.1.0 dataset (https://gnomad.broadinstitute.org/variant/2-55647424-C-T?dataset=gnomad_r4). While we suspect this variant is likely benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.