ClinVar Miner

Submissions for variant NM_001909.5(CTSD):c.758A>G (p.Lys253Arg) (rs138191189)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187315 SCV000240897 uncertain significance not provided 2013-02-13 criteria provided, single submitter clinical testing p.Lys253Arg (AAG>AGG): c.758 A>G in exon 6 of the CTSD gene (NM_001909.3)The c.758 A>G substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Multiple in silico models predict that the c.758 A>G substitution could potentially create a new cryptic splice donor site that may supplant the natural site and lead to abnormal splicing. In the absence of RNA/functional studies, the actual effect of the c.758 A>G sequence change on splicing is unknown. If c.758 A>G does not alter splicing, it is predicted to result in a Lys253Arg missense substitution, which is a conservative change since both Lysine and Arginine are positively charged amino acids. Lys253Arg alters a poorly conserved position in the protein, and several in silico algorithms predict it may be benign, although one model suggests it may be damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether c.758 A>G is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV001041227 SCV001204829 uncertain significance Neuronal ceroid lipofuscinosis 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 253 of the CTSD protein (p.Lys253Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs138191189, ExAC 0.07%). This variant has not been reported in the literature in individuals with CTSD-related conditions. ClinVar contains an entry for this variant (Variation ID: 205358). 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 tolerated, 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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