ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.407G>A (p.Arg136His) (rs769701646)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000454168 SCV000537961 likely pathogenic Abnormality of brain morphology criteria provided, single submitter research
Genetic Services Laboratory, University of Chicago RCV000499595 SCV000594156 uncertain significance not specified 2015-10-29 criteria provided, single submitter clinical testing
Invitae RCV001379796 SCV001577667 likely pathogenic Neuronal ceroid lipofuscinosis 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 136 of the CLN6 protein (p.Arg136His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 27903347, 26075876, 30561534). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 402184). 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. This variant disrupts the p.Arg136 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 19135028), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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