Submissions for variant NM_000310.4(PPT1):c.529C>G (p.Gln177Glu)

gnomAD frequency: 0.00003  dbSNP: rs386833650

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188719	SCV000242343	pathogenic	not provided	2022-03-30	criteria provided, single submitter	clinical testing	Reported previously in individuals with late-infantile neuronal ceroid lipofuscinosis who harbored a second PPT1 variant in unknown phase (Das et al., 1998; Waliany et al., 2000); Published functional studies demonstrate significantly reduced enzyme activity in the presence of the Q177E mutation (Das et al., 2001); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19793631, 10649502, 12125808, 21990111, 11073228, 9664077, 11440996)
Invitae	RCV000049609	SCV000762916	pathogenic	Neuronal ceroid lipofuscinosis 1	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 177 of the PPT1 protein (p.Gln177Glu). This variant is present in population databases (rs386833650, gnomAD 0.008%). This missense change has been observed in individual(s) with late onset neuronal ceroid lipofuscinoses (PMID: 9664077). ClinVar contains an entry for this variant (Variation ID: 56198). 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 PPT1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000188719	SCV000861264	pathogenic	not provided	2018-05-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000049609	SCV000915409	pathogenic	Neuronal ceroid lipofuscinosis 1	2017-04-28	criteria provided, single submitter	clinical testing	The PPT1 c.529C>G (p.Gln177Glu) missense variant has been reported in a compound heterozygous state in five unrelated individuals with neuronal ceroid lipofuscinosis (NCL) (Das et al. 1998; Waliany et al. 2000; Kousi et al. 2012). Three individuals were affected with late-infantile NCL with the age of onset not reported in the other two subjects. The p.Gln177Glu variant was absent from 60 controls subjects but is reported at a frequency of 0.00007 in the European (non-Finnish) population of the Exome Aggregation Consortium. An enzyme activity of 7.3% of normal was detected in COS cells transfected with the p.Gln177Glu variant, while enzyme levels of 1.08% that of control was detected in lymphoblasts from an individual carrying the p.Gln177Glu variant (Das et al. 2001). Furthermore, kinetic analysis on highly purified variant protein using Sf9 insect cells revealed that the p.Gln177Glu variant led to substrate binding defects compared to wild type (Das et al. 2001). Based on the evidence, the p.Gln177Glu variant is classified as pathogenic for autosomal recessive neuronal ceroid lipofuscinosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000049609	SCV004204165	pathogenic	Neuronal ceroid lipofuscinosis 1	2024-01-19	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049609	SCV000082016	probable-pathogenic	Neuronal ceroid lipofuscinosis 1		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.