Submissions for variant NM_000391.4(TPP1):c.833A>G (p.Gln278Arg)

gnomAD frequency: 0.00001  dbSNP: rs796053439

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189774	SCV000243422	pathogenic	not provided	2013-02-21	criteria provided, single submitter	clinical testing	p.Gln278Arg (Q278R) CAG>CGG: c.833 A>G in exon 7 of the TPP1 gene (NM_000391.3)The Q278R missense mutation in the TPP1 gene has been reported previously in two siblings with myoclonicastatic epilepsy and abnormal TPP1 enzyme analysis who had a second disease-causing mutation on the other allele (Lemke et al., 2012). Additionally, a different missense substitution at the same codon, Q278P, has been reported as a disease-causing mutation in a patient with electron microscopy findings consistent with neuronal ceroid lipofuscinosis (Ju et al., 2002). The Q278R amino acid substitution is non-conservative, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Therefore, Q278R is considered to be a disease-causing mutation. The variant is found in CHILD-EPI,PME-EPI panel(s).
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000209853	SCV000265552	pathogenic	Neuronal ceroid lipofuscinosis 2	2015-02-10	criteria provided, single submitter	research
Counsyl	RCV000209853	SCV000798809	likely pathogenic	Neuronal ceroid lipofuscinosis 2	2018-03-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000189774	SCV002284287	likely pathogenic	not provided	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 278 of the TPP1 protein (p.Gln278Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 22612257). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 207582). 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%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235113	SCV003934487	likely pathogenic	Neuronal ceroid lipofuscinosis	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: TPP1 c.833A>G (p.Gln278Arg) results in a conservative amino acid change located in the Sedolisin domain (IPR030400) of the encoded protein sequence. Four 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 251460 control chromosomes. c.833A>G has been reported in the literature in compound heterozygous individuals affected with or with clinical features of Neuronal Ceroid-Lipofuscinosis (Batten Disease) including with evidence of familial segregation and in trans with a pathogenic variant (Lemke_2012, Bowling_2017, Lindy_2018). These data indicate that the variant may 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: 28554332, 22612257, 29655203). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.