ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.1304C>T (p.Thr435Met)

gnomAD frequency: 0.00001  dbSNP: rs28933376
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000014718 SCV001533915 likely pathogenic Familial hemophagocytic lymphohistiocytosis 2 2023-09-04 criteria provided, single submitter clinical testing This variant is present in population databases (rs28933376, gnomAD 0.009%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 435 of the PRF1 protein (p.Thr435Met). 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. 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. Experimental studies have shown that this missense change affects PRF1 function (PMID: 18927437, 19487666). ClinVar contains an entry for this variant (Variation ID: 13717). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 12599189, 25233452, 32542393). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002260966 SCV002542765 likely pathogenic Autoinflammatory syndrome 2022-02-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473103 SCV004204178 likely pathogenic Aplastic anemia 2023-10-26 criteria provided, single submitter clinical testing
OMIM RCV000014718 SCV000034973 pathogenic Familial hemophagocytic lymphohistiocytosis 2 2003-03-15 no assertion criteria provided literature only

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