Submissions for variant NM_001083116.3(PRF1):c.147C>A (p.Asp49Glu)

dbSNP: rs761310644

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV001370616	SCV001499915	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2020-12-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001370616	SCV001567137	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 49 of the PRF1 protein (p.Asp49Glu). This variant is present in population databases (rs761310644, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of hemophagocytic lymphohistiocytosis (PMID: 33942430, 34170459; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1012308). 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. This variant disrupts the p.Asp49 amino acid residue in PRF1. Other variant(s) that disrupt this residue have been observed in individuals with PRF1-related conditions (PMID: 22186995), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690071	SCV005185401	uncertain significance	not specified	2024-05-30	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.147C>A (p.Asp49Glu) results in a conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247816 control chromosomes. c.147C>A has been reported in the literature in the compound heterozygous state in individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Guan_2021, Hao_2021, Li_2023). These data indicate that the variant may 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: 34170459, 33942430). ClinVar contains an entry for this variant (Variation ID: 1012308). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.