Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001732821 | SCV001983530 | likely pathogenic | Familial hemophagocytic lymphohistiocytosis | 2021-09-03 | criteria provided, single submitter | clinical testing | Variant summary: PRF1 c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of four in-silico tools predict a benign effect and two predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-06 in 185260 control chromosomes (gnomAD). c.3G>A has been reported in the literature in individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Feldmann_2002, Molleran Lee_2004, Zur Stadt_2006). In one of the compound heterozygous patients with the variant, perforin protein expression in NK cells was found to be <1% (Molleran Lee_2004). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Other missense variants affecting the initiation codon of PRF1 are reported in HGMD as disease-associated and are cited in ClinVar as pathogenic (e.g. p.Met1Thr, p.Met1Val). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV001861038 | SCV002233568 | pathogenic | Familial hemophagocytic lymphohistiocytosis 2 | 2024-01-01 | criteria provided, single submitter | clinical testing | This sequence change affects the initiator methionine of the PRF1 mRNA. The next in-frame methionine is located at codon 288. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 12060139, 12716377, 26199792, 29095814). ClinVar contains an entry for this variant (Variation ID: 1301336). For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV001861038 | SCV005087101 | pathogenic | Familial hemophagocytic lymphohistiocytosis 2 | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hemophagocytic lymphohistiocytosis type 2 (MIM#603553). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 3 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the initiation codon, is present in gnomAD (v1: 1 heterozygote, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported both as homozygous and compound heterozygous in at least ten patients with familial hemophagocytic lymphohistiocytosis type 2 (MIM#603553) (PMID: 17873118, 23592409). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |