ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1340G>A (p.Arg447His) (rs119455956)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189790 SCV000243438 pathogenic not provided 2015-08-18 criteria provided, single submitter clinical testing p.Arg447His (CGT>CAT): c.1340 G>A in exon 11 of the TPP1 gene (NM_000391.3)The Arg447His missense mutation has been observed in multiple patients with neuronal ceroid-lipofuscuinosis 2 (CLN2) who harbored a second disease causing mutation on the other chromosome (Sleat et al., 1999). Although this mutation is a conservative substitution of one positively charged polar amino acid for another, it alters a conserved region of the TPP1 protein and other mutations at nearby codons have been reported in association with CLN2. In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the Arg477His is considered a disease-causing mutation in the TPP1 gene. The variant is found in EPILEPSY panel(s).
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000002764 SCV000746792 pathogenic Ceroid lipofuscinosis neuronal 2 2017-12-18 criteria provided, single submitter clinical testing
Invitae RCV001053458 SCV001217719 pathogenic Neuronal ceroid lipofuscinosis 2020-01-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 447 of the TPP1 protein (p.Arg447His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs119455956, ExAC 0.003%). This variant has been observed to segregate with neuronal ceroid lipofuscinosis in families (PMID: 10330339, 20340139). ClinVar contains an entry for this variant (Variation ID: 2645). This variant has been reported to affect TPP1 protein function (PMID: 20340139). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002764 SCV000022922 pathogenic Ceroid lipofuscinosis neuronal 2 1999-06-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000002764 SCV000091187 not provided Ceroid lipofuscinosis neuronal 2 no assertion provided not provided

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