ClinVar Miner

Submissions for variant NM_007315.3(STAT1):c.796G>A (p.Val266Ile) (rs41473544)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000585895 SCV000425823 benign Immunodeficiency 31a 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 Mycobacterial and viral infections, susceptibility to, autosomal recessive; Immunodeficiency 31C; Immunodeficiency 31a 2019-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000762307 SCV000892612 likely benign not provided 2018-06-01 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000539213 SCV000898999 uncertain significance Mycobacterial and viral infections, susceptibility to, autosomal recessive; Immunodeficiency 31C; Immunodeficiency 31a 2018-10-24 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 Mycobacterial and viral infections, susceptibility to, autosomal recessive 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000585895 SCV000693864 pathogenic Immunodeficiency 31a 2018-10-04 no assertion criteria provided literature only

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