ClinVar Miner

Submissions for variant NM_003978.5(PSTPIP1):c.764C>T (p.Thr255Met)

gnomAD frequency: 0.00002  dbSNP: rs766895096
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489849 SCV000577488 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing The T255M variant in the PSTPIP1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T255M variant is observed in 1/63804 (0.002%) alleles from individuals of European Non-Finnish background in the ExAC dataset (Lek et al., 2016). The T255M 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 in the F-BAR domain that is not conserved across species. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T255M as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001036647 SCV001200022 uncertain significance Pyogenic arthritis-pyoderma gangrenosum-acne syndrome 2023-11-01 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 255 of the PSTPIP1 protein (p.Thr255Met). This variant is present in population databases (rs766895096, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of PAPA syndrome (PMID: 34273117). ClinVar contains an entry for this variant (Variation ID: 426913). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PSTPIP1 protein function with a negative predictive value of 80%. 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.

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