Submissions for variant NM_000391.4(TPP1):c.617G>A (p.Arg206His)

gnomAD frequency: 0.00001  dbSNP: rs121908209

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001200081	SCV000548744	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 206 of the TPP1 protein (p.Arg206His). This variant is present in population databases (rs121908209, gnomAD 0.0009%). This missense change has been observed in individual(s) with TPP1-related conditions (PMID: 12698559; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 68748). 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.Arg206 amino acid residue in TPP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10665500, 20340139, 30541466). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001200081	SCV001370944	likely pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001200081	SCV002020272	likely pathogenic	not provided	2021-07-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354256	SCV002656849	uncertain significance	Inborn genetic diseases	2018-02-28	criteria provided, single submitter	clinical testing	The p.R206H variant (also known as c.617G>A), located in coding exon 6 of the TPP1 gene, results from a G to A substitution at nucleotide position 617. The arginine at codon 206 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported in an individual with late infantile neuronal ceroid lipofuscinosis (CLN2); however, clinical details were limited (Kousi M. Hum. Mutat.. 2012 Jan;33(1):42-63). 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.
UniProtKB/Swiss-Prot	RCV000059630	SCV000091198	not provided	Neuronal ceroid lipofuscinosis 2		no assertion provided	not provided
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000469057	SCV000804934	pathogenic	Neuronal ceroid lipofuscinosis	2012-08-29	no assertion criteria provided	clinical testing