Submissions for variant NM_007315.4(STAT1):c.796G>A (p.Val266Ile)

gnomAD frequency: 0.00251  dbSNP: rs41473544

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000585895	SCV000425823	benign	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000539213	SCV000655077	likely benign	Immunodeficiency 31B; Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome; Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2024-01-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000762307	SCV000892612	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	STAT1: PP2, BP4, BS3:Supporting, BS2
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000539213	SCV000898999	uncertain significance	Immunodeficiency 31B; Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome; Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2021-03-30	criteria provided, single submitter	clinical testing	STAT1 NM_007315.3 exon 10 p.Val266Ile (c.796G>A): This variant has been reported in the literature as a heterozygous variant in at least 8 individuals with varying [inconsistent?] immunodeficiency phenotypes (Uzel 2013 PMID:23534974, Mork 2015 PMID:26513235, Remaschi 2015 PMID:26162368, Szymanski 2015 PMID:26038974, Depner 2016 PMID:26604104, Rae 2018 PMID:29077208). This variant is present in 0.6% (175/25748) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-191859935-C-T) and is present in ClinVar with conflicting interpretations ranging from likely benign to pathogenic (Variation ID:333285). Functional studies are also conflicting; one study using flow cytometric anaylsis showed a significant increase in STAT1 phosphorylation with this variant compared to the wildtype, which is consistent with a gain of function effect (Uzel 2013 PMID:23534974). However, a second study using similar methodology showed no evidence for hyperphosphorylation of STAT1 with this variant (Depner 2016 PMID:26604104). This variant amino acid Isoleucine (Ile) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Mendelics	RCV000986961	SCV001136124	likely benign	Immunodeficiency 31B	2019-05-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000762307	SCV001713258	uncertain significance	not provided	2020-06-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530342	SCV004737308	uncertain significance	STAT1-related disorder	2023-11-28	criteria provided, single submitter	clinical testing	The STAT1 c.796G>A variant is predicted to result in the amino acid substitution p.Val266Ile. This variant has been reported in the heterozygous state in individuals with various immunodeficiency phenotypes including symptoms reminiscent of IPEX syndrome (Patient 4, Uzel et al. 2013. PubMed ID: 23534974), herpes simplex encephalitis (Patients 7 and 8, Mørk et al. 2015. PubMed ID: 26513235), pulmonary nontuberculous mycobacterial infection (Supplementary Table E4, Szymanski et al. 2015. PubMed ID: 26038974), chronic mucocutaneous candidiasis (Sporadic Patient, Spor10, Depner et al. 2016. PubMed ID: 26604104), and primary immunodeficiency (Patient 26, also had a variant in TNFRSF13B, Rae et al. 2018. PubMed ID: 29077208). However, this variant is reported in 0.68% of alleles in individuals of European (Finnish) descent in gnomAD, including three homozygous individuals. Functional studies have shown that the p.Val266Ile variant leads to increased STAT1 phosphorylation as compared to wildtype, which is consistent with a gain of function variant (Uzel et al. 2013. PubMed ID: 23534974). However, other functional studies have shown no impact on STAT phosphorylation as a result of the p.Val266Ile variant (Depner et al. 2016. PubMed ID: 26604104). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM	RCV000585895	SCV000693864	pathogenic	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	2018-10-04	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000762307	SCV001963478	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000762307	SCV001967664	likely benign	not provided		no assertion criteria provided	clinical testing