ClinVar Miner

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

gnomAD frequency: 0.00061  dbSNP: rs137852695
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Total submissions: 12
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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 2014-09-07 criteria provided, single submitter clinical testing
Invitae RCV000009450 SCV000762929 pathogenic Neuronal ceroid lipofuscinosis 1 2021-12-09 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%). 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPT1 function (PMID: 7637805, 10781062). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
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
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

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