ClinVar Miner

Submissions for variant NM_001909.5(CTSD):c.283G>A (p.Val95Ile) (rs141482597)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483803 SCV000573549 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CTSD gene. The V95I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V95I variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V95I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000796838 SCV000936367 uncertain significance Neuronal ceroid lipofuscinosis 2020-02-17 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 95 of the CTSD protein (p.Val95Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs141482597, ExAC 0.02%). This variant has not been reported in the literature in individuals with CTSD-related conditions. ClinVar contains an entry for this variant (Variation ID: 423805). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Illumina Clinical Services Laboratory,Illumina RCV001106639 SCV001263720 uncertain significance Neuronal ceroid lipofuscinosis 10 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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