Submissions for variant NM_004937.3(CTNS):c.517T>C (p.Tyr173His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003783688	SCV004571040	likely pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 173 of the CTNS protein (p.Tyr173His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystinosis (PMID: 28983406). 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 expected to disrupt CTNS protein function with a positive predictive value of 80%. This variant disrupts the p.Tyr173 amino acid residue in CTNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21786142, 30214781, 35571017). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV004527465	SCV005038895	likely pathogenic	Nephropathic cystinosis	2024-03-14	criteria provided, single submitter	clinical testing