ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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
Counsyl RCV000009450 SCV000677944 pathogenic Ceroid lipofuscinosis neuronal 1 2015-06-06 criteria provided, single submitter clinical testing
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
GeneReviews RCV000009450 SCV000086760 pathologic Ceroid lipofuscinosis neuronal 1 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000009450 SCV000762929 pathogenic Ceroid lipofuscinosis neuronal 1 2018-11-16 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.
OMIM RCV000009450 SCV000029668 pathogenic Ceroid lipofuscinosis neuronal 1 1995-08-17 no assertion criteria provided literature only

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