ClinVar Miner

Submissions for variant NM_000310.3(PPT1):c.364A>T (p.Arg122Trp) (rs137852695)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188724 SCV000242348 pathogenic not provided 2017-04-07 criteria provided, single submitter clinical testing The R122W variant in the PPT1 gene is a founder mutation in the Finnish population and has also been reported multiple times in patients of other ethnicities with a clinical diagnosis of NCL (Vesa et al., 1995; Das et al., 1998; Kousi et al., 2012). This variant alters a highly conserved residue, and functional studies indicate it significantly impairs enzyme activity (Vesa et al., 1995). Therefore, R122W is considered a disease-causing variant
Ambry Genetics RCV000623227 SCV000740797 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000009450 SCV000762929 pathogenic Neuronal ceroid lipofuscinosis 1 2019-05-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 122 of the PPT1 protein (p.Arg122Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs137852695, ExAC 0.7%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported as homozygous and in combination with another PPT1 variant in many individuals affected with infantile neuronal ceroid lipofuscinosis (INCL, PMID: 7637805, 26795593, 9664077). It is the most common INCL disease variant, and has been suggested as a founder variant in the Finnish population (PMID: 19941651, 21990111). ClinVar contains an entry for this variant (Variation ID: 8899). Experimental studies have shown that this missense change leads to a misfolded protein and disrupts PPT1 enzyme activity (PMID: 10781062, 7637805). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Myriad Women's Health, 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.
Integrated Genetics/Laboratory Corporation of America 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.
OMIM RCV000009450 SCV000029668 pathogenic Neuronal ceroid lipofuscinosis 1 1995-08-17 no assertion criteria provided literature only
GeneReviews RCV000009450 SCV000086760 pathologic Neuronal ceroid lipofuscinosis 1 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
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

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