Submissions for variant NM_000391.4(TPP1):c.197A>T (p.Gln66Leu)

gnomAD frequency: 0.00001  dbSNP: rs751088292

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189755	SCV000243403	uncertain significance	not provided	2014-02-06	criteria provided, single submitter	clinical testing	p.Gln66Leu (CAG>CTG): c.197 A>T in exon 3 of the TPP1 gene (NM_000391.3)A variant of unknown significance has been identified in the TPP1 gene. The Q66L 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 Q66L 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. However, in silico analysis predicts the Q66L variant likely does not alter 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 EPILEPSYV2-1 panel(s).
Ambry Genetics	RCV002415815	SCV002723556	uncertain significance	Inborn genetic diseases	2017-08-28	criteria provided, single submitter	clinical testing	The p.Q66L variant (also known as c.197A>T), located in coding exon 3 of the TPP1 gene, results from an A to T substitution at nucleotide position 197. The glutamine at codon 66 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000189755	SCV003505625	uncertain significance	not provided	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 66 of the TPP1 protein (p.Gln66Leu). This variant is present in population databases (rs751088292, gnomAD 0.003%). 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: 207565). 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 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.
CeGaT Center for Human Genetics Tuebingen	RCV000189755	SCV004135868	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	TPP1: BP4
Natera, Inc.	RCV001833127	SCV002094883	uncertain significance	Neuronal ceroid lipofuscinosis 2	2019-11-11	no assertion criteria provided	clinical testing