ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 339 of the TPP1 protein (p.Arg339Trp). This variant is present in population databases (rs750428882, gnomAD 0.003%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 24091540; 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: 207586). 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.Arg339 amino acid residue in TPP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22832778, 23266810). 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.

The c.1015C>T (p.R339W) alteration is located in exon 8 (coding exon 8) of the TPP1 gene. This alteration results from a C to T substitution at nucleotide position 1015, causing the arginine (R) at amino acid position 339 to be replaced by a tryptophan (W). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in the homozygous state, and in conjunction with another alteration in TPP1, in multiple individuals with clinical features of neuronal ceroid lipofuscinosis (Gowda, 2021; Dozieres-Puyravel, 2020; Sheth, 2018; Ohba, 2013). Additionally, another missense variant at the same codon, c.1016G>A (p.R339Q), has been described in individuals with neuronal ceroid lipofuscinosis (Sheth 2018; Butler, 2017; Kohan, 2013). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, R339W is deleterious. The variant is moderately destabilizing to the local structure and more destabilizing than a nearby pathogenic variant (Pal, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29655203, 31589614, 30541466, 38730490, 38101904, 24091540, 31489614, 34849271, 33356800, 31440721, 33528536)

Variant summary: TPP1 c.1015C>T (p.Arg339Trp) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251430 control chromosomes. c.1015C>T has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Gowda_2021, Dozieres-Puyravel_2020, Ohba_2013). In addition, another missense variant in the same residue (p.Arg339Gln) has been classified as pathogenic/likely pathogenic in Clinvar supporting the functional importance of this residue of protein. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31489614, 34849271, 24091540). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neuronal ceroid lipofuscinosis 2 (MIM#204500) and spinocerebellar ataxia 7 (MIM#609270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated peptidase_S8 domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Arg339Gln)) has been reported once as a VUS, but many times as likely pathogenic and pathogenic. Another comparable variant (p.(Arg339Leu)) has been reported once as both likely pathogenic and a VUS (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and observed in individuals with neuronal ceroid lipofuscinosis (ClinVar, PMID: 34849271, PMID: 31489614). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign