Submissions for variant NM_000391.4(TPP1):c.380G>A (p.Arg127Gln)

dbSNP: rs121908204

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494361	SCV000583376	likely pathogenic	not provided	2020-07-16	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 20340139, 25525159, 11339651, 21990111, 12376936, 29631617, 15317752)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281905	SCV000920326	likely pathogenic	Neuronal ceroid lipofuscinosis	2022-08-18	criteria provided, single submitter	clinical testing	Variant summary: TPP1 c.380G>A (p.Arg127Gln) results in a conservative amino acid change located in the Peptidase S53, activation domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. As the nucleotide change corresponds to an exonic splice-region (last nucleotide of exon 4), several computational tools predict a significant impact on normal splicing: Five predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Steinfeld_2004). The variant was absent in 251472 control chromosomes (gnomAD). c.380G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Steinfeld_2004, Zhong_2000, Worgall_2007, Sima_2018, Nickel_2018, Lukacs_2019). These data indicate that the variant is likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal enzymatic activity (Steinfeld_2004, Walus_2010). Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000494361	SCV001495513	likely pathogenic	not provided	2023-10-26	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 127 of the TPP1 protein (p.Arg127Gln). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 11339651, 12376936, 17679671, 30119717, 30771299; Invitae). ClinVar contains an entry for this variant (Variation ID: 68746). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TPP1 function (PMID: 15317752, 20340139). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000059628	SCV002072992	likely pathogenic	Neuronal ceroid lipofuscinosis 2		criteria provided, single submitter	clinical testing	The missense variant p.R127Q in TPP1 (NM_000391.4) has been previously observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (Zhong et al., 2000; Worgall et al., 2007; Steinfeld et al., 2002). The p.R127Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant also falls at the last nucleotide of exon 4 of the TPP1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Likely Pathogenic.
UniProtKB/Swiss-Prot	RCV000059628	SCV000091195	not provided	Neuronal ceroid lipofuscinosis 2		no assertion provided	not provided
Counsyl	RCV000059628	SCV000793438	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2017-08-16	no assertion criteria provided	clinical testing