ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.278C>T (p.Thr93Met) (rs150001589)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187115 SCV000240690 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing According to the NCL Mutation Database, the T93M missense change was previously identified in a patient with adult-onset neuronal ceroid lipofusinosis who had a second CLN6 variant; however, information about parental testing was not provided (NCL Mutation Database; Kousi et al., 2012). Additionally, T93M has been reported as possibly disease-causing in a patient with suspected mitochondrial disease who was compound heterozygous for T93M and a second CLN6 variant (DeRa et al., 2013). The T93M variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The T93M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. It alters a highly conserved position in the second transmembrane domain of the protein (Kousi et al., 2012), and multiple in silico algorithms predict it may be damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000803649 SCV000943530 uncertain significance Neuronal ceroid lipofuscinosis 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 93 of the CLN6 protein (p.Thr93Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs150001589, ExAC 0.004%). This variant has been observed in individuals affected with neuronal ceroid lipofuscinosis (PMID: 24215330, 21990111, 30561534). ClinVar contains an entry for this variant (Variation ID: 205183). 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). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000187115 SCV001247327 likely pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing

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