Submissions for variant NM_139276.3(STAT3):c.1979T>C (p.Met660Thr)

dbSNP: rs886039434

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255312	SCV000321952	likely pathogenic	not provided	2016-03-22	criteria provided, single submitter	clinical testing	The M660T variant has been published in association with hyper IgE syndrome (Schimke et al., 2010). The M660T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M660T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position located within the SH2 domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586892	SCV000699917	likely pathogenic	Hyper-IgE syndrome	2016-08-15	criteria provided, single submitter	clinical testing	Variant summary: The STAT3 c.1979T>C (p.Met660Thr) variant involves the alteration of a conserved nucleotide located in the Src homology domain 2 of STAT3 and results in a replacement of a medium size and hydrophobic Methionine (M) with a medium size and polar Threonine (T). 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121612 control chromosomes while it was reported in Hyper IgE Syndrome patients indicating pathogenicity. Moreover, in one patient, the variant emerged de novo strongly suggesting a deleterious outcome. Studies assessing the impact the variant may have on the function of the STAT3 protein were not published at the time of classification. Taken together, this variant is classified as probably pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792133	SCV000931411	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2018-09-10	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change disrupts protein function (PMID: 28315006, 29868029). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met660 amino acid residue in STAT3. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 21792878), which suggests that this may be a clinically significant amino acid residue. This variant has been observed in individuals affected with hyper IgE syndrome, including an individual in which the variant occurred de novo (PMID: PMID: 20816194, 28315006). ClinVar contains an entry for this variant (Variation ID: 265261). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 660 of the STAT3 protein (p.Met660Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine.
Mayo Clinic Laboratories, Mayo Clinic	RCV000255312	SCV005413217	pathogenic	not provided	2024-02-26	criteria provided, single submitter	clinical testing	PP2, PP3, PM1, PM2, PM6, PS3_supporting, PS4
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000586892	SCV005420520	pathogenic	Hyper-IgE syndrome	2024-10-04	criteria provided, single submitter	research	PS2,PS3,PM2,PP3