ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1526A>G (p.Gln509Arg) (rs149529997)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764996 SCV000896179 uncertain significance Ceroid lipofuscinosis neuronal 2; Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000189793 SCV000243441 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing p.Gln509Arg (CAG>CGG): c.1526 A>G in exon 12 of the TPP1 gene (NM_000391.3) The Q509R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Q509R variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The Q509R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Missense mutations in nearby residues (G501C, N504Y) have been reported in association with neuronal ceroid lipofuscinosis supporting the functional importance of this region of the protein. However, this substitution occurs at a position that is not conserved across species and Arginine is observed at this position in one species in distant evolution. Additionally, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in EPILEPSY panel(s).
Invitae RCV000632684 SCV000753870 uncertain significance Neuronal ceroid lipofuscinosis 2018-08-01 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 509 of the TPP1 protein (p.Gln509Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs149529997, ExAC 0.1%). This variant has not been reported in the literature in individuals with TPP1-related disease. ClinVar contains an entry for this variant (Variation ID: 207594). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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