Submissions for variant NM_139276.3(STAT3):c.1234-4dup

gnomAD frequency: 0.00011  dbSNP: rs763332844

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781884	SCV000920267	benign	not specified	2018-11-01	criteria provided, single submitter	clinical testing	Variant summary: STAT3 c.1234-4dupA alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.7e-05 in 277168 control chromosomes (gnomAD). The observed variant frequency is approximately 21-fold above the estimated maximal expected allele frequency for a pathogenic variant in STAT3 causing Hyper IgE Syndrome phenotype (2.2e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1234-4dupA in individuals affected with Hyper IgE Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001437691	SCV001640551	likely benign	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2023-08-14	criteria provided, single submitter	clinical testing