ClinVar Miner

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

gnomAD frequency: 0.00109  dbSNP: rs146571352
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766604 SCV000252116 uncertain significance not provided 2023-07-24 criteria provided, single submitter clinical testing Observed in a patient with mitochondrial encephalopathy in published literature (Pennisi et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26633545, 33199448, 34498404)
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 2023-05-01 criteria provided, single submitter clinical testing PNPT1: BP4
Invitae 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.

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