ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.255C>G (p.Phe85Leu) (rs545955828)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187090 SCV000240665 uncertain significance not provided 2014-03-12 criteria provided, single submitter clinical testing p.Phe85Leu (TTC>TTG): c.255 C>G in exon 3 of the CLN6 gene (NM_017882.2). The Phe85Leu 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 6500 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 Phe85Leu variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Illumina Clinical Services Laboratory,Illumina RCV001118064 SCV001276318 uncertain significance Neuronal ceroid lipofuscinosis 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001118064 SCV001417592 uncertain significance Neuronal ceroid lipofuscinosis 2019-05-09 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 85 of the CLN6 protein (p.Phe85Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs545955828, ExAC 0.01%). This variant has not been reported in the literature in individuals with CLN6-related disease. ClinVar contains an entry for this variant (Variation ID: 205162). 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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