Submissions for variant NM_000391.4(TPP1):c.1610G>A (p.Cys537Tyr)

dbSNP: rs777744177

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189802	SCV000243450	uncertain significance	not provided	2014-11-19	criteria provided, single submitter	clinical testing	p.Cys537Tyr (TGC>TAC): c.1610 G>A in exon 13 of the TPP1 gene (NM_000391.3) The C537Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It 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 C537Y 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 that is conserved across species. Missense mutations in nearby residues (G535R, P544S, W548R) have been reported in association with neuronal ceroid lipofuscinosis supporting the functional importance of this region of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae	RCV000189802	SCV002222686	uncertain significance	not provided	2022-02-12	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 537 of the TPP1 protein (p.Cys537Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 207602). 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 TPP1 protein function. 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.
Natera, Inc.	RCV001828012	SCV002094789	uncertain significance	Neuronal ceroid lipofuscinosis 2	2021-09-22	no assertion criteria provided	clinical testing