ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1016G>A (p.Arg339Gln) (rs765380155)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625040 SCV000744908 likely pathogenic Ceroid lipofuscinosis neuronal 2 2016-06-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000180153 SCV000232543 uncertain significance not provided 2014-09-17 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000625040 SCV000743598 likely pathogenic Ceroid lipofuscinosis neuronal 2 2017-07-28 criteria provided, single submitter clinical testing
Invitae RCV000699225 SCV000827926 pathogenic Neuronal ceroid lipofuscinosis 2018-04-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 339 of the TPP1 protein (p.Arg339Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs765380155, ExAC 0.001%). This variant has been reported as homozygous or in combination with another TPP1 variant in individuals with low TPP1 enzyme activities, findings that are highly specific for CLN2 (PMID: 22832778, 23266810). ClinVar contains an entry for this variant (Variation ID: 198725). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. A different missense substitution at this codon (p.Pro339Trp) has been determined to be pathogenic (PMID: 24091540, Invitae). 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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