Submissions for variant NM_017882.3(CLN6):c.119C>T (p.Thr40Met) (rs769199442)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414428	SCV000491774	uncertain significance	not specified	2016-11-10	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CLN6 gene. The T40M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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. The T40M 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. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000801841	SCV000941639	uncertain significance	Neuronal ceroid lipofuscinosis	2020-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 40 of the CLN6 protein (p.Thr40Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs769199442, ExAC 0.03%). This variant has not been reported in the literature in individuals with CLN6-related disease. ClinVar contains an entry for this variant (Variation ID: 373196). 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: Possibly Damaging; Align-GVGD: Class C1). 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. 5

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