ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.472G>A (p.Ala158Thr) (rs386833723)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187031 SCV000240604 uncertain significance not provided 2014-02-14 criteria provided, single submitter clinical testing p.Ala158Thr (GCT>ACT): c.472 G>A in exon 8 of the CLN3 gene (NM_001042432.1). The Ala158Thr variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry, indicating it is not a common benign variant in these populations. The Ala158Thr variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species in the lumen loop between the third and fourth transmembrane segments of the CLN3 protein and in silico analysis predicts this variant is probably damaging to the protein structure/function. A different amino acid substitution at the same position (Ala158Pro) has been reported in an individual with juvenile neuronal ceroid lipofuscinosis; however, a second mutation in the CLN3 gene was not identified (Kousi et al., 2012) . Based on the currently available information, it is unclear whether Ala158Thr is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000689160 SCV000816800 uncertain significance Neuronal ceroid lipofuscinosis 2018-03-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 158 of the CLN3 protein (p.Ala158Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CLN3-related disease. ClinVar contains an entry for this variant (Variation ID: 205110). 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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