Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000702712 | SCV000831577 | likely pathogenic | Immunodeficiency 31B; Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome; Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency | 2018-07-16 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glycine at codon 274 of the STAT1 protein (p.Arg274Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. 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. Two different missense substitution at this codon (p.Arg274Gln and p.Arg274Trp) have been determined to be pathogenic (PMID: 21714643, 21727188, 22195034, 22847544, 25367169, 26604104, 26242301, 28258222). This suggests that the arginine residue is critical for STAT1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies using transfected cells have shown that this missense change causes results in delayed dephosphorylation, enhanced DNA binding, and enhanced transactivation of STAT1 after IFN-γ and IFN-α stimulation (PMID: 23541320). This variant has been reported in an individual affected with oral candidiasis and disseminated histoplasmosis (PMID: 23541320). ClinVar contains an entry for this variant (Variation ID: 160354). This variant is not present in population databases (ExAC no frequency). |
| 3billion | RCV000148020 | SCV002058966 | pathogenic | Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome | 2022-01-03 | criteria provided, single submitter | clinical testing | Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:23541320, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030083,VCV000030085, PMID:21714643,21727188, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.835, 3CNET: 0.99, PP3_P). A missense variant is a common mechanism associated with Immunodeficiency 31C (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
| OMIM | RCV000148020 | SCV000195520 | pathogenic | Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome | 2013-06-01 | no assertion criteria provided | literature only |