ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.1018G>A (p.Asp340Asn)

gnomAD frequency: 0.00001  dbSNP: rs754079962
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong RCV001257084 SCV001364384 likely pathogenic Familial hemophagocytic lymphohistiocytosis 2 2020-06-02 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001257084 SCV002178520 uncertain significance Familial hemophagocytic lymphohistiocytosis 2 2022-09-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 340 of the PRF1 protein (p.Asp340Asn). This variant is present in population databases (rs754079962, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of hemophagocytic lymphohistiocytosis (PMID: 25577959, 32963807, 33746956). ClinVar contains an entry for this variant (Variation ID: 929472). 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323810 SCV004028871 likely pathogenic Familial hemophagocytic lymphohistiocytosis 2023-07-28 criteria provided, single submitter clinical testing Variant summary: PRF1 c.1018G>A (p.Asp340Asn) results in a conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250892 control chromosomes. c.1018G>A has been reported in the literature as a biallelic homozygous genotype in at-least two individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, Mhatre_2015, Fung_2020, Shabrish_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32963807, 25577959, 33746956). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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