ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.229G>A (p.Gly77Arg)

gnomAD frequency: 0.00002  dbSNP: rs121908195
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001731479 SCV000920325 pathogenic Neuronal ceroid lipofuscinosis 2021-09-15 criteria provided, single submitter clinical testing Variant summary: TPP1 c.229G>A (p.Gly77Arg) results in a non-conservative amino acid change located in the Peptidase S53, activation domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250960 control chromosomes. c.229G>A has been reported in the literature in individuals affected with Late-Infantile Neuronal Ceroid-Lipofuscinoses (Sleat_1999, Wisniewski_2001, Kousi_2011, Nickel_2018). Functional studies showed the variant with total cellular activity in expressing cells at about 1% of wild-type TPPI value and both the folding difficulties and impaired specific activity may underlie the disease process in subjects carrying the p.Gly77Arg mutation (Sleat_1999; Wisniewski_2001; Walus_2010). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001854253 SCV002238476 pathogenic not provided 2022-06-27 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects TPP1 function (PMID: 20340139). 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. ClinVar contains an entry for this variant (Variation ID: 68744). This variant has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 10330339, 21990111). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 77 of the TPP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TPP1 protein. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon.
UniProtKB/Swiss-Prot RCV000059626 SCV000091193 not provided Neuronal ceroid lipofuscinosis 2 no assertion provided not provided

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