ClinVar Miner

Submissions for variant NM_001909.5(CTSD):c.796C>T (p.Arg266Cys) (rs373621431)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187316 SCV000240898 uncertain significance not provided 2014-01-29 criteria provided, single submitter clinical testing p.Arg266Cys (CGC>TGC): c.796 C>T in exon 6 of the CTSD gene (NM_001909.4). The Arg266Cys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with a uncharged Cysteine and the gain of a Cystine may affect the formation of disulfide bonds in the CTSD protein. The Arg266Cys variant alters a position that is well conserved across species in the Cathepsin D heavy chain of the CTSD protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, there have been no reported mutations in this region of the CTSD protein. Therefore, based on the currently available information, it is unclear whether Arg266Cys is a disease-causing mutation or a rare benign variant.The variant is found in EPILEPSY panel(s).
Invitae RCV000817194 SCV000957742 uncertain significance Neuronal ceroid lipofuscinosis 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 266 of the CTSD protein (p.Arg266Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs373621431, ExAC 0.002%). This variant has not been reported in the literature in individuals with CTSD-related conditions. ClinVar contains an entry for this variant (Variation ID: 205359). 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.

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