Submissions for variant NM_005430.4(WNT1):c.521T>C (p.Ile174Thr)

dbSNP: rs758928266

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433696	SCV000530353	uncertain significance	not provided	2017-11-22	criteria provided, single submitter	clinical testing	The I174T variant in the WNT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I174T variant was not observed in approximately 6500 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 I174T 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 where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I174T as a variant of uncertain significance.
3billion	RCV005252893	SCV005904716	uncertain significance	Osteogenesis imperfecta type 15	2024-02-20	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.72 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.