Submissions for variant NM_012448.4(STAT5B):c.2171C>T (p.Thr724Met)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV003320425	SCV004024508	uncertain significance	Growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant	2023-07-03	criteria provided, single submitter	clinical testing	This STAT5B missense variant (rs139131471) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 9/282736 total alleles; 0.003%; no homozygotes). It has not been reported in ClinVar, nor the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be damaging. Of note, these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. The threonine residue at this position is evolutionarily conserved across many of the species assessed. We consider the clinical significance of c.2171C>T in STAT5B to be uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003505333	SCV004307719	uncertain significance	Growth hormone insensitivity with immune dysregulation 1, autosomal recessive	2023-02-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 724 of the STAT5B protein (p.Thr724Met). This variant is present in population databases (rs139131471, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with STAT5B-related conditions. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.