ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.829G>A (p.Val277Met)

dbSNP: rs121908207
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001778699 SCV002015102 likely pathogenic Neuronal ceroid lipofuscinosis 2021-10-28 criteria provided, single submitter clinical testing Variant summary: TPP1 c.829G>A (p.Val277Met) results in a conservative amino acid change located in the Sedolisin domain (IPR030400) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, structural studies predicted this variant as destabilization of alpha 8 and might affect active site (Pal_2009, Guhaniyogi_2009). The variant was absent in 251454 control chromosomes (gnomAD). c.829G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Ju_2002, Sleat_2016). These data indicate that the variant may be associated with disease. At least one functional study reports this variant showed no measurable TPPI activity (Walus_2010). Additionally, missense variants in nearby residues (L275P, D276V, Q278R, Q278Q) have been reported in the Human Gene Mutation Database in association with Neuronal ceroid lipofuscinosis, supporting the functional importance of this region of the protein. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
UniProtKB/Swiss-Prot RCV000059631 SCV000091199 not provided Neuronal ceroid lipofuscinosis 2 no assertion provided not provided

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