Submissions for variant NM_000391.4(TPP1):c.616C>T (p.Arg206Cys)

gnomAD frequency: 0.00001  dbSNP: rs28940573

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382645	SCV001581521	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg206 amino acid residue in TPP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12698559; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TPP1 function (PMID: 20340139). 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. ClinVar contains an entry for this variant (Variation ID: 2646). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 22832778, 30541466). This variant is present in population databases (rs28940573, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 206 of the TPP1 protein (p.Arg206Cys).
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000002765	SCV002754481	pathogenic	Neuronal ceroid lipofuscinosis 2		criteria provided, single submitter	clinical testing	A Homozygous missense variation in exon 6 of the TPP1 gene that results in the amino acid substitution of Cysteine for Arginine at codon 206 was detected. The observed variant c.616C>T (p.Arg206Cys) has not been reported in the 1000 genomes and has MAF of 0.001% in gnomAD databases. The in silico prediction of the variant are possibly damaging by DANN, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Revvity Omics, Revvity	RCV001382645	SCV003820413	pathogenic	not provided	2022-04-12	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000002765	SCV005060865	pathogenic	Neuronal ceroid lipofuscinosis 2		criteria provided, single submitter	clinical testing	The observed missense c.616C>T(p.Arg206Cys) variant in TPP1 gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with Neuronal ceroid lipofuscinoses type II (NCL2) / Batten disease (Sheth et al., 2018). Experimental studies have shown that this missense change affects TPP1 function (Walus et al., 2010). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Arg at position 206 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg206Cys in TPP1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000002765	SCV000022923	pathogenic	Neuronal ceroid lipofuscinosis 2	2000-02-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000002765	SCV000091197	not provided	Neuronal ceroid lipofuscinosis 2		no assertion provided	not provided
Natera, Inc.	RCV000002765	SCV002094863	pathogenic	Neuronal ceroid lipofuscinosis 2	2020-03-10	no assertion criteria provided	clinical testing