Submissions for variant NM_000310.4(PPT1):c.364A>T (p.Arg122Trp)

gnomAD frequency: 0.00061  dbSNP: rs137852695

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188724	SCV000242348	pathogenic	not provided	2022-07-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect resulting in impairment of enzyme activity (Lyly et al., 2007; Vesa et al., 1995); 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: 20561933, 22778232, 14997939, 11754099, 26026925, 16759889, 24997880, 16542649, 12069847, 19793631, 26795593, 9664077, 17388982, 10781062, 20346914, 16644870, 19941651, 16930952, 11073228, 25091425, 25865307, 7637805, 25525159, 21228398, 21990111, 28559085, 31980526, 17565660, 33726816)
Ambry Genetics	RCV000623227	SCV000740797	pathogenic	Inborn genetic diseases	2016-05-02	criteria provided, single submitter	clinical testing	The p.R122W pathogenic mutation (also known as c.364A>T), located in coding exon 4 of the PPT1 gene, results from an A to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by tryptophan, an amino acid with dissimilar properties. This pathogenic mutation has been identified in the homozygous state or with another alteration in PPT1 in multiple individuals with infantile neuronal ceroid lipofuscinoses (NCL) and is a founder mutation in the Finnish population (Vesa J et al. Nature. 1995; 376(6541):584-7; Das AK et al. J Clin Invest. 1998; 102(2):361-70; Kousi M et al. Hum Mutat. 2012; 33(1):42-63). Functional studies in patient cells and in vitro studies have found this mutation to result in undetectable enzyme activity and accumulation of the polypeptide in the endoplasmic reticulum (Vesa J et al. Nature. 1995; 376(6541):584-7; Das AK et al. Hum Mol Genet. 2001;10(13):1431-9; Lyly A et al. BMC Cell Biol. 2007; 8:22). In addition, based on structural analysis, this mutation is anticipated to result in a significant decrease in structural stability (Bellizzi JJ et al. Proc Natl Acad Sci USA. 2000; 97(9):4573-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000009450	SCV000762929	pathogenic	Neuronal ceroid lipofuscinosis 1	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 122 of the PPT1 protein (p.Arg122Trp). This variant is present in population databases (rs137852695, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with infantile neuronal ceroid lipofuscinosis (INCL) (PMID: 7637805, 9664077, 26795593). It is commonly reported in individuals of Finnish ancestry (PMID: 7637805, 9664077, 19941651, 21990111, 26795593; INCL). ClinVar contains an entry for this variant (Variation ID: 8899). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPT1 function (PMID: 7637805, 10781062). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000009450	SCV001194212	pathogenic	Neuronal ceroid lipofuscinosis 1	2019-12-09	criteria provided, single submitter	clinical testing	NM_000310.3(PPT1):c.364A>T(R122W) is classified as pathogenic in the context of PPT1-related neuronal ceroid lipofuscinosis and is associated with the infantile form of this disease. Sources cited for classification include the following: PMID 7637805. Classification of NM_000310.3(PPT1):c.364A>T(R122W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000009450	SCV001363469	pathogenic	Neuronal ceroid lipofuscinosis 1	2019-05-06	criteria provided, single submitter	clinical testing	Variant summary: PPT1 c.364A>T (p.Arg122Trp) results in a non-conservative amino acid change in 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 0.0007 in 250432 control chromosomes (gnomAD). c.364A>T has been reported in the literature in numerous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and is considered a Finnish founder mutation. The variant has been functionally shown to impact enzyme activity (Vesa_1995). 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000009450	SCV001571359	pathogenic	Neuronal ceroid lipofuscinosis 1	2021-04-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000188724	SCV001712988	pathogenic	not provided	2019-12-13	criteria provided, single submitter	clinical testing	PS3, PS4, PM3, PP4, PP5
Fulgent Genetics, Fulgent Genetics	RCV000009450	SCV002780411	pathogenic	Neuronal ceroid lipofuscinosis 1	2021-09-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000009450	SCV003826604	pathogenic	Neuronal ceroid lipofuscinosis 1	2022-06-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000009450	SCV004204129	pathogenic	Neuronal ceroid lipofuscinosis 1	2023-10-16	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV000009450	SCV005849009	pathogenic	Neuronal ceroid lipofuscinosis 1	2025-02-19	criteria provided, single submitter	clinical testing	ACMG: PS3_Supporting, PM2_Supporting, PM3_Strong, PP3_Strong, PP4_Strong
OMIM	RCV000009450	SCV000029668	pathogenic	Neuronal ceroid lipofuscinosis 1	1995-08-17	no assertion criteria provided	literature only
GeneReviews	RCV000009450	SCV000086760	not provided	Neuronal ceroid lipofuscinosis 1		no assertion provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000581618	SCV000692330	pathogenic	Neuronal ceroid lipofuscinosis	2011-07-06	no assertion criteria provided	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000009450	SCV001142297	pathogenic	Neuronal ceroid lipofuscinosis 1	2020-01-06	no assertion criteria provided	curation	NM_000310.3:c.364A>T in the PPT1 gene has an allele frequency of 0.006 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that c.364A>T has impaired enzyme activity(PMID: 7637805). Helbig et al. reported a child with progressive Myoclonus Epilepsy barboring the compound heterozygous of c.364A>T (p.R122W) and c.353G>A (p.G118D) (PMID: 26795593); In addition, Vesa et al. reported that 40 of the 42 Finnish families, whose child were homozygous suffering Ceroid lipofuscinosis neuronal, and parents were heterozygous, suggesting a founder effect in Finnish population (PMID: 7637805); Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS4; PS3; PM3; PP4
Natera, Inc.	RCV000009450	SCV001464020	pathogenic	Neuronal ceroid lipofuscinosis 1	2020-09-16	no assertion criteria provided	clinical testing