ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.749G>A (p.Arg250His) (rs554594996)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187104 SCV000240679 uncertain significance not provided 2015-06-22 criteria provided, single submitter clinical testing p.Arg250His (CGC>CAC): c.749 G>A in exon 7 of the CLN6 gene (NM_017882.2). The Arg250His missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Arg250His in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative, as Arginine and Histidine are both positively charged amino acids. It alters a position between the sixth and seventh transmembrane domains that is conserved through mammals but is not conserved in more distant species. Several in silico algorithms predict it may be damaging to protein structure/function, although another model suggests it may be benign. Therefore, based on the currently available information, it is unclear whether Arg250His is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000544507 SCV000628983 uncertain significance Neuronal ceroid lipofuscinosis 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 250 of the CLN6 protein (p.Arg250His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs554594996, 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: 205175). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; 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.

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