ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: 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).
Labcorp Genetics (formerly Invitae), Labcorp RCV000817194 SCV000957742 uncertain significance Neuronal ceroid lipofuscinosis 2022-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 266 of the CTSD protein (p.Arg266Cys). This variant is present in population databases (rs373621431, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CTSD-related conditions. ClinVar contains an entry for this variant (Variation ID: 205359). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTSD protein function. 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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