ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.182T>G (p.Leu61Arg) (rs1060502179)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465968 SCV000548741 likely pathogenic Neuronal ceroid lipofuscinosis 2017-02-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 61 of the TPP1 protein (p.Leu61Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TPP1-related disease. This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual with deficient TPP1 enzyme levels and phenotypic characteristics of autosomal recessive neuronal ceroid lipofuscinosis type 2 (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that has been observed in trans from a pathogenic variant in an individual with specific indications for autosomal recessive neuronal ceroid lipofuscinosis type 2. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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