Submissions for variant NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln)

gnomAD frequency: 0.00001  dbSNP: rs765380155

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180153	SCV000232543	uncertain significance	not provided	2014-09-17	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625040	SCV000743598	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625040	SCV000744908	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2016-06-17	criteria provided, single submitter	clinical testing
Invitae	RCV000180153	SCV000827926	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 339 of the TPP1 protein (p.Arg339Gln). This variant is present in population databases (rs765380155, gnomAD 0.0009%). This missense change has been observed in individual(s) with TPP1-related conditions (PMID: 22832778, 23266810). ClinVar contains an entry for this variant (Variation ID: 198725). 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 with a positive predictive value of 95%. This variant disrupts the p.Pro339 amino acid residue in TPP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24091540; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000625040	SCV001737219	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000180153	SCV001778011	likely pathogenic	not provided	2020-10-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32298681, 30541466, 29056246, 23266810, 21990111, 19038966)
Human Genetics Research Lab, Central University of Jammu	RCV000625040	SCV001762275	pathogenic	Neuronal ceroid lipofuscinosis 2	2021-07-29	no assertion criteria provided	research	We confirmed the missense variation NC_00011.10:g.6616374C>T (NP_000382.3:p.Arg339Gln; rs765380155) in exon 8 of TPP1 gene, segregating with disease in family and in silico analyses predicted the variant to be highly pathogenic that corelated with pathologically low enzymatic activity of TPP1 in the proband's blood sample (<0.49 μmol/L/h; pathological reference = <0.5 μmol/L/h). Reference source OMIM: 204500 Neuronal ceroid lipofuscinosis-2 is caused by homozygous or compound heterozygous mutation in the TPP1 gene (607998) on chromosome 11p15. Reference source ClinVar: RCV000699225.1 NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln) and Neuronal ceroid lipofuscinosis https://www.ncbi.nlm.nih.gov/clinvar/RCV000699225.1/
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000180153	SCV001808621	likely pathogenic	not provided		no assertion criteria provided	clinical testing