Submissions for variant NM_007315.4(STAT1):c.800C>T (p.Ala267Val)

dbSNP: rs387906759

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684865	SCV000812325	pathogenic	Immunodeficiency 31B; Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome; Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 267 of the STAT1 protein (p.Ala267Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant chronic mucocutaneous candidiasis (PMID: 21714643, 23709754, 24343863, 26255980, 26494717, 26604104). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30084). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects STAT1 function (PMID: 23541320, 26255980). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825629	SCV000966986	pathogenic	Chronic mucocutaneous candidiasis	2018-05-04	criteria provided, single submitter	clinical testing	The p.Ala267Val variant in STAT1 has been reported in >10 individuals with chron ic mucocutaneous candidiasis (CMC) and segregated with disease in 16 individuals from 9 families (Liu 2011, van de Veerdonk 2011, Sampaio 2013, Mizoguchi 2014, Nielsen 2015, Zheng 2015, Depner 2016, Breuer 2017, Dadak 2017). It was absent f rom large population studies. Additionally, in vitro functional studies support a pathogenic role (Sampaio 2013, Mizoguchi 2014, Zheng 2015). In summary, the p. Ala267Val variant meets criteria to be classified as pathogenic for CMC in an au tosomal dominant manner. ACMG/AMP Criteria applied: PP1_Strong; PM2; PS4_Moderat e; PP3; PS3_Supporting.
Baylor Genetics	RCV001337084	SCV001530653	pathogenic	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2018-09-12	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as a pathogenic variant with gain-of-function disease mechanisms [PMID 21714643, 28427548, 28161409, 26604104, 28815025, 24343863, 26494717, 23541320, 26255980]
GeneDx	RCV001701570	SCV002513161	pathogenic	not provided	2024-07-29	criteria provided, single submitter	clinical testing	Reported in unrelated individuals with autosomal dominant STAT1-related immunodeficiency in the published literature (PMID: 24343863, 21714643, 26604104, 28427548); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28161409, 34619682, 26494717, 26255980, 28815025, 28427548, 26604104, 21714643, 30187709, 32146551, 32888943, 34738677, 35753512, 35840326, 34390440, 32009323, 24343863, 23541320)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000022987	SCV003806978	pathogenic	Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome	2022-06-21	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP1 strong, PP2 supporting
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV004760338	SCV005374006	pathogenic	Immunodeficiency 31B	2024-09-22	criteria provided, single submitter	clinical testing
OMIM	RCV000022987	SCV000044278	pathogenic	Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome	2013-06-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701570	SCV001932384	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001701570	SCV001951520	pathogenic	not provided		no assertion criteria provided	clinical testing