ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.64G>A (p.Ala22Thr) (rs527373013)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187112 SCV000240687 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing p.Ala22Thr (GCC>ACC): c.64 G>A in exon 1 of the CLN6 gene (NM_017882.2). The Ala22Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Ala22Thr alters a position that is not conserved in the signal peptide domain of the CLN6 protein and several in-silico algorithms predict it may be benign. However, other missense mutations in this region of the protein have been reported in association with late-infantile neuronal ceroid lipofuscinosis (NCL) and the amino acid substitution is non-conservative as a non-polar Alanine residue is replaced by a polar Threonine residue. Therefore, based on the currently available information, it is unclear whether Ala22Thr is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000813039 SCV000953372 uncertain significance Neuronal ceroid lipofuscinosis 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 22 of the CLN6 protein (p.Ala22Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with CLN6-related conditions. ClinVar contains an entry for this variant (Variation ID: 205181). 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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