ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.649C>A (p.Leu217Met) (rs150913606)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187033 SCV000240606 uncertain significance not provided 2015-04-03 criteria provided, single submitter clinical testing p.Leu217Met (CTG>ATG): c.649 C>A in exon 9 of the CLN3 gene (NM_001042432.1)The Leu217Met missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Leu217Met alters a conserved position in the fifth transmembrane domain of the Battenin protein and several in-silico algorithms predict it may be damaging to the structure/function of the protein. However, the amino acid substitution is conservative as both Leucine and Methionine are uncharged, non-polar amino acid residues. Therefore, based on the currently available information, it is unclear whether Leu217Met is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI,CHILD-EPI panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000346618 SCV000396329 uncertain significance Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000533590 SCV000628936 uncertain significance Neuronal ceroid lipofuscinosis 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 217 of the CLN3 protein (p.Leu217Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs150913606, ExAC 0.01%) but has not been reported in the literature in individuals with a CLN3-related disease. ClinVar contains an entry for this variant (Variation ID: 205112). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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