ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.775G>A (p.Gly259Ser) (rs150363441)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001235065 SCV001407729 uncertain significance Neuronal ceroid lipofuscinosis 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 259 of the CLN6 protein (p.Gly259Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs150363441, ExAC 0.002%). This variant has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Gly259 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 19135028, 31489614), which suggests that this may be a clinically significant amino acid residue. 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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV001375037 SCV001571713 likely pathogenic Neuronal ceroid lipofuscinosis 6 2021-02-12 criteria provided, single submitter clinical testing A homozygous missense variant in exon 7 of the CLN6 gene that results in the amino acid substitution of Serine for Glycine at codon 259 was detected. The observed variant c.775G>A (p.Leu83Val) has not been reported in the 1000 genomes and has a MAF of 0.0024% in gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
GeneDx RCV001561994 SCV001784694 uncertain significance not provided 2020-02-24 criteria provided, single submitter clinical testing Identified in a patient with suspected mitochondrial disease who also had a second CLN6 variant in trans (DaRe et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Different missense changes at this residue (G259C; G259V; G259D) reported in association with NCL in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24215330, 21990111)

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