ClinVar Miner

Submissions for variant NM_001909.5(CTSD):c.817C>T (p.His273Tyr) (rs145905196)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000420091 SCV000535467 uncertain significance not provided 2018-06-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CTSD gene. The H273Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The H273Y 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 H273Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with CTSD-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001037357 SCV001200767 uncertain significance Neuronal ceroid lipofuscinosis 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 273 of the CTSD protein (p.His273Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs145905196, ExAC 0.01%). This variant has not been reported in the literature in individuals with CTSD-related conditions. ClinVar contains an entry for this variant (Variation ID: 392231). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). 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. 5
Baylor Genetics RCV001335880 SCV001529133 uncertain significance Neuronal ceroid lipofuscinosis 10 2018-04-11 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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