ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.134G>A (p.Gly45Glu)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003516322 SCV004294737 likely pathogenic Familial hemophagocytic lymphohistiocytosis 2 2023-02-25 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 45 of the PRF1 protein (p.Gly45Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 14757862). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRF1 protein function. Experimental studies have shown that this missense change affects PRF1 function (PMID: 15755897, 16374518). This variant disrupts the p.Gly45 amino acid residue in PRF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11756153, 29357941, 30697212; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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