ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.316C>T (p.Arg106Cys) (rs202226970)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724319 SCV000230372 uncertain significance not provided 2014-11-05 criteria provided, single submitter clinical testing
GeneDx RCV000724319 SCV000240669 uncertain significance not provided 2013-09-30 criteria provided, single submitter clinical testing p.Arg106Cys (CGC>TGC): c.316 C>T in exon 4 of the CLN6 gene (NM_017882.2). The Arg106Cys missense change in the CLN6 gene 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. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged Cysteine residue, and the addition of a Cysteine may alter disulfide bonds and the secondary structure of the protein. However, the variant alters a position in the protein that is not conserved across species. 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 Arg106Cys is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000458041 SCV000549212 uncertain significance Neuronal ceroid lipofuscinosis 2019-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 106 of the CLN6 protein (p.Arg106Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs202226970, ExAC 0.009%). This variant has not been reported in the literature in individuals with CLN6-related disease. ClinVar contains an entry for this variant (Variation ID: 197315). 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 disruptive, 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.
Illumina Clinical Services Laboratory,Illumina RCV000458041 SCV001274725 uncertain significance Neuronal ceroid lipofuscinosis 2018-01-13 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.

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