10-70599026-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_001083116.3(PRF1):โc.695G>Aโ(p.Arg232His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,398 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001083116.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRF1 | NM_001083116.3 | c.695G>A | p.Arg232His | missense_variant | 3/3 | ENST00000441259.2 | |
PRF1 | NM_005041.6 | c.695G>A | p.Arg232His | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRF1 | ENST00000441259.2 | c.695G>A | p.Arg232His | missense_variant | 3/3 | 5 | NM_001083116.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152236Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000639 AC: 16AN: 250342Hom.: 0 AF XY: 0.0000887 AC XY: 12AN XY: 135340
GnomAD4 exome AF: 0.0000411 AC: 60AN: 1461162Hom.: 1 Cov.: 35 AF XY: 0.0000550 AC XY: 40AN XY: 726794
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74386
ClinVar
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The PRF1 c.695G>A (p.Arg232His) missense variant has been described in six studies in individuals with familial hemophagocytic lymphohistiocytosis (FHL) (Feldman et al. 2002; Zur Stadt et al. 2006; Busiello et al. 2007; Cannella et al. 2007; Zhang et al. 2011; Sieni et al. 2012). The p.Arg232His variant was detected in a compound heterozygous state with a missense variant in two individuals and in a compound heterozygous state as part of a complex allele involving a p.Ala91Val variant in an additional five individuals. One unaffected individual was also found to be compound heterozygous for the p.Arg232His and p.Ala91Val variants, though not as part of a complex allele. The p.Arg232His variant was further detected in a heterozygous state in two affected individuals. The p.Arg232His variant was absent from 50 controls but is reported at a frequency of 0.00042 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Arg232His variant resulted in reduced or no detectable perforin expression, only partial processing to the mature form of the protein, and only 27 รขโฌโ 30% of wild type cytotoxic activity (Feldman et al. 2002; Voskoboinik et al. 2005; Risma et al. 2006; Zhang et al. 2011; Sieni E et al. 2012). The complex allele was shown to be completely inactive (Voskoboinik et al. 2005). The evidence for this variant in isolation is limited. The p.Arg232His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 232 of the PRF1 protein (p.Arg232His). This variant is present in population databases (rs747380397, gnomAD 0.03%). This missense change has been observed in individual(s) with anaplastic large cell lymphoma and hemophagocytic lymphohistiocytosis and/or hemophagocytic lymphohistiocytosis (PMID: 12060139, 14739222, 16278825, 21881043, 22970278, 24309606, 26342526; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 300331). 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. Experimental studies have shown that this missense change affects PRF1 function (PMID: 15755897, 16374518, 19487666). This variant disrupts the p.Arg232 amino acid residue in PRF1. Other variant(s) that disrupt this residue have been observed in individuals with PRF1-related conditions (PMID: 33225392, 33746956), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Aplastic anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at