Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000043.6(FAS):c.695A>G(p.Tyr232Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]
Autoimmune lymphoproliferative syndrome, type 1a Pathogenic:1
Feb 01, 1997
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
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Autoimmune lymphoproliferative syndrome type 1 Uncertain:1
Aug 22, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. Experimental studies have shown that this missense change interferes with the function of Fas protein (PMID: 20935634, 26942442). This variant has been observed to segregate with autoimmune lymphoproliferative syndrome in a family (PMID: 9028321). ClinVar contains an entry for this variant (Variation ID: 16503). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosin with cysteine at codon 232 of the FAS protein (p.Tyr232Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosin and cysteine -