ClinVar Miner

Submissions for variant NM_000270.3(PNP):c.701G>C (p.Arg234Pro) (rs104894451)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000419921 SCV000520983 likely pathogenic not provided 2016-02-11 criteria provided, single submitter clinical testing The R234P variant in the PNP gene has been reported previously in association with PNP deficiency in six unrelated individuals who were compound heterozygous for the R234P variant and another pathogenic variant (Aust et al., 1992; Markert et al., 1997; Walker et al., 2011). The R234P variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R234P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Lysates from cells transfected with the R234P variant had no detectable human PNP activity (Aust et al., 1992). The R234P variant is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000015028 SCV000815640 likely pathogenic Purine-nucleoside phosphorylase deficiency 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 234 of the PNP protein (p.Arg234Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs104894451, ExAC 0.02%). This variant has been reported in several individuals affected with purine nucleoside phosphorylase deficiency, all of whom also carried a second rare variant in the PNP gene (PMID: 1384322, 9067751, 22132981). ClinVar contains an entry for this variant (Variation ID: 13991). Experimental studies of cells transfected with the R234P variant showed that this missense change abolished human PNP enzymatic activity (PMID: 1384322). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000015028 SCV000915636 pathogenic Purine-nucleoside phosphorylase deficiency 2018-10-18 criteria provided, single submitter clinical testing The c.702G>C (p.Arg234Pro) missense variant has been reported in three studies in which it was found in a total of five individuals with purine nucleoside phosphorylase (PNP) deficiency, including in four individuals in a compound heterozygous state and in one individual in a heterozygous state in whom a second variant identified was not identified (Aust et al. 1992; Markert et al. 1997; Walker et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transfection of the variant protein into COS cells demonstrated that the variant resulted in no detectable PNP activity (Aust et al. 1992). Based on the evidence, the p.Arg234Pro variant is classified as pathogenic for purine nucleoside phosphorylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000015028 SCV000035284 pathogenic Purine-nucleoside phosphorylase deficiency 1997-01-01 no assertion criteria provided literature only

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