ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.196C>T (p.Gln66Ter) (rs759080581)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189754 SCV000243402 pathogenic not provided 2019-01-08 criteria provided, single submitter clinical testing The Q66X variant in the TPP1 gene has been reported previously in the homozygous state or in the presence of a second TPP1 variant in individuals with neuronal ceroid lipofuscinosis (Sleat et al, 1999; Kohan et al., 2009). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q66X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Q66X as a pathogenic variant.
Invitae RCV000824347 SCV000965243 pathogenic Neuronal ceroid lipofuscinosis 2018-08-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln66*) in the TPP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs759080581, ExAC 0.003%). This variant has been observed to be homozygous or in combination with another TPP1 variant in individuals affected with neuronal ceroid lipofuscinosis (PMID: 10330339, 23266810). ClinVar contains an entry for this variant (Variation ID: 207564). Loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000824347 SCV001361224 pathogenic Neuronal ceroid lipofuscinosis 2019-10-25 criteria provided, single submitter clinical testing Variant summary: TPP1 c.196C>T (p.Gln66X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251320 control chromosomes (gnomAD). c.196C>T has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, e.g. Sleat_1999, Kohan_2009). These data indicate that the variant is likely to be associated with disease. TPP1 enzyme activity has been reported as deficient in cells with the variant (Sleat_1999). Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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