ClinVar Miner

Submissions for variant NM_000310.3(PPT1):c.223A>C (p.Thr75Pro) (rs137852696)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188709 SCV000242333 pathogenic not provided 2018-06-28 criteria provided, single submitter clinical testing p.Thr75Pro (ACC>CCC): c.223 A>C in exon 2 of the PPT1 gene (NM_000310.3). The Thr75Pro missense substitution in the PPT1 gene is a common mutation that has been reported in multiple individuals with juvenile neuronal ceroid lipofuscinosis (NCL) who harbored a second mutation on the other allele (in trans) (Mitchison et al., 1998; Kousi et al., 2012). The variant is found in CHILD-EPI panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000009451 SCV000918089 pathogenic Neuronal ceroid lipofuscinosis 1 2018-11-16 criteria provided, single submitter clinical testing Variant summary: PPT1 c.223A>C (p.Thr75Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 246324 control chromosomes (gnomAD).The variant, c.223A>C, has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease), including at least one homozygote (Mitchison_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Women's Health, Inc. RCV000009451 SCV001193860 pathogenic Neuronal ceroid lipofuscinosis 1 2019-12-09 criteria provided, single submitter clinical testing NM_000310.3(PPT1):c.223A>C(T75P) is classified as pathogenic in the context of PPT1-related neuronal ceroid lipofuscinosis and is associated with the juvenile form of this disease. Sources cited for classification include the following: PMID 9425237, 9664077 and 23539563. Classification of NM_000310.3(PPT1):c.223A>C(T75P) 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.
Invitae RCV000009451 SCV001397118 pathogenic Neuronal ceroid lipofuscinosis 1 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 75 of the PPT1 protein (p.Thr75Pro). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs137852696, ExAC 0.01%). This variant has been observed in several individuals affected with neuronal ceroid lipofuscinosis 1 (PMID: 9425237, 26510000, 28559085). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8900). This variant has been reported to affect PPT1 protein function in patient derived cell lines (PMID: 23539563). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009451 SCV000029669 pathogenic Neuronal ceroid lipofuscinosis 1 1998-07-15 no assertion criteria provided literature only

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