ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.1164C>A (p.Ser388Arg)

dbSNP: rs761607073
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001822676 SCV002071863 uncertain significance not specified 2021-09-22 criteria provided, single submitter clinical testing DNA sequence analysis of the PRF1 gene demonstrated a sequence change, c.1164C>A, in exon 3 that results in an amino acid change, p.Ser388Arg. This sequence change has not been described in population databases including ExAC and gnomAD. The p.Ser388Arg change affects a moderately conserved amino acid residue located in a domain of the PRF1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser388Arg substitution. This sequence change does not appear to have been previously described in individuals with PRF1-related disorders, however, a different amino acid change at the same position, p.Ser388Ile, has been reported in an individual with severe aplastic anemia (PMID: 17311987). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser388Arg change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV002542676 SCV003479620 uncertain significance Familial hemophagocytic lymphohistiocytosis 2 2022-04-12 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 388 of the PRF1 protein (p.Ser388Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1338078). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.

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