ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1015C>T (p.Arg339Trp) (rs750428882)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720076 SCV000850952 likely pathogenic Seizures 2016-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Structural Evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
GeneDx RCV000189779 SCV000243427 likely pathogenic not provided 2016-08-09 criteria provided, single submitter clinical testing The R339W variant in the TPP1 gene has been reported in trans with another TPP1 variant in a patient with epilepsy, ataxia, intellectual disability and low activity of tripeptidyl peptidaste 1 (Ohba et al., 2013). The R339W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The R339W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and is predicted to play a role in hydrogen bond formation and protein folding (Pal et al., 2009). In silico analysis predicts this variant is probably damaging to the protein structure/function . A different missense pathogenic variant at the same residue, R339Q, has been reported in multiple individuals with neuronal ceroid lipofuscinosis 2 (Kohan et al., 2013; Kousi et al., 2012). The R339W variant is a strong candidate for a pathogenic variant.
Invitae RCV000552528 SCV000628892 pathogenic Neuronal ceroid lipofuscinosis 2017-05-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 339 of the TPP1 protein (p.Arg339Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs750428882, ExAC 0.01%). This variant has been reported in an individual with neuronal ceroid lipofuscinosis (PMID: 24091540). This variant occurs on the opposite chromosome with a pathogenic variant (p.Gly389Glu) in TPP1 in an individual with autosomal recessive neuronal ceroid lipofuscinosis type 2 (Invitae). ClinVar contains an entry for this variant (Variation ID: 207586). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg339Gln) has been determined to be pathogenic (PMID: 22832778, 23266810). This suggests that the arginine residue is critical for TPP1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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