ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.1225A>G (p.Met409Val) (rs776443981)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187022 SCV000240595 uncertain significance not provided 2014-01-31 criteria provided, single submitter clinical testing p.Met409Val (ATG>GTG): c.1225 A>G in exon 16 of the CLN3 gene (NM_001042432.1). The Met409Val missense change 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 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Met409Val variant alters a well conserved region across species in the cytoplasmic C-terminus region of the CLN3 protein and a nearby missense mutation has been reported in this region of the CLN3 protein in association with neuronal ceroid lipofuscinosis (Kousi et al., 2012). In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant is a conservative substitution of one uncharged non-polar amino acid for another. Therefore, based on the currently available information, it is unclear whether Met409Val is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000692993 SCV000820846 uncertain significance Neuronal ceroid lipofuscinosis 2018-04-03 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 409 of the CLN3 protein (p.Met409Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs776443981, ExAC 0.02%). This variant has not been reported in the literature in individuals with CLN3-related disease. ClinVar contains an entry for this variant (Variation ID: 205101). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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