rs137852695
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP4
The NM_000310.4(PPT1):c.364A>T(p.Arg122Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000310.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.364A>T | p.Arg122Trp | missense_variant, splice_region_variant | 4/9 | ENST00000642050.2 | NP_000301.1 | |
PPT1 | NM_001363695.2 | c.364A>T | p.Arg122Trp | missense_variant, splice_region_variant | 4/8 | NP_001350624.1 | ||
PPT1 | NM_001142604.2 | c.125-1886A>T | intron_variant | NP_001136076.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.364A>T | p.Arg122Trp | missense_variant, splice_region_variant | 4/9 | NM_000310.4 | ENSP00000493153 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000598 AC: 91AN: 152110Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000703 AC: 176AN: 250432Hom.: 0 AF XY: 0.000724 AC XY: 98AN XY: 135374
GnomAD4 exome AF: 0.000298 AC: 436AN: 1460870Hom.: 0 Cov.: 32 AF XY: 0.000297 AC XY: 216AN XY: 726742
GnomAD4 genome AF: 0.000598 AC: 91AN: 152228Hom.: 0 Cov.: 31 AF XY: 0.000927 AC XY: 69AN XY: 74414
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Pathogenic:10Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 17, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Apr 12, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 06, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 23, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 17, 2022 | - - |
Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | 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 - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 09, 2019 | 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 13, 2019 | PS3, PS4, PM3, PP4, PP5 - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2016 | 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. - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jul 06, 2011 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at