Submissions for variant NM_033109.5(PNPT1):c.2213G>A (p.Arg738His)

gnomAD frequency: 0.00001  dbSNP: rs574670461

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001290310	SCV001478357	likely pathogenic	Combined oxidative phosphorylation defect type 13	2019-12-12	criteria provided, single submitter	clinical testing
Invitae	RCV001871733	SCV002204497	uncertain significance	not provided	2021-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 738 of the PNPT1 protein (p.Arg738His). This variant is present in population databases (rs574670461, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with PNPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 996028). 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. 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	RCV001871733	SCV002549264	uncertain significance	not provided	2022-08-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Neuberg Centre For Genomic Medicine, NCGM	RCV003448389	SCV004176651	uncertain significance	Autosomal recessive nonsyndromic hearing loss 70	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.2213G>A (p.Arg738His) variant in PNPT1 gene has been submitted to ClinVar as a Variant of Uncertain Significance / Likely pathogenic. The p.Arg738His variant has allele frequency 0.02% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid change p.Arg738His in PNPT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 738 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
PreventionGenetics, part of Exact Sciences	RCV004545186	SCV004779459	likely benign	PNPT1-related disorder	2022-11-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).