ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.1337A>C (p.Gln446Pro)

gnomAD frequency: 0.00002  dbSNP: rs751161742
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000196330 SCV000255442 likely pathogenic Familial hemophagocytic lymphohistiocytosis 2 2014-04-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000196330 SCV001233846 pathogenic Familial hemophagocytic lymphohistiocytosis 2 2023-06-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 216986). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 25326637, 26450956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs751161742, gnomAD 0.01%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 446 of the PRF1 protein (p.Gln446Pro).
Baylor Genetics RCV003474966 SCV004204175 pathogenic Aplastic anemia 2023-12-02 criteria provided, single submitter clinical testing
GeneDx RCV004719747 SCV005325385 likely pathogenic not provided 2024-03-10 criteria provided, single submitter clinical testing Reported with a second PRF1 variant in patients with familial hemophagocytic lymphohistiocytosis; it is not known if the variants are on the same allele (in cis) or opposite alleles (in trans) (PMID: 26450956); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 25326637, 32542393, 32638196, 34938098, 26450956)

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