ClinVar Miner

Submissions for variant NM_001909.5(CTSD):c.751G>A (p.Asp251Asn) (rs763407972)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187314 SCV000240896 likely pathogenic not provided 2013-05-14 criteria provided, single submitter clinical testing p.Asp251Asn (GAC>AAC): c.751 G>A in exon 6 of the CTSD gene (NM_001909.3)The Asp251Asn missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is a non-conservative as a negatively charged Aspartic acid residue is replaced with an uncharged Asparagine residue. Asp251Asn alters a highly conserved position located in the Cathepsin D heavy chain. While one in silico algorithm predicts Asp251Asn may be benign, multiple others predict that it may be damaging to the protein structure/function. Therefore, based on the currently available information, Asp251Asn is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded. The variant is found in CHILD-EPI panel(s).
Invitae RCV000541141 SCV000628954 uncertain significance Neuronal ceroid lipofuscinosis 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 251 of the CTSD protein (p.Asp251Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs763407972, ExAC 0.009%) but has not been reported in the literature in individuals with a CTSD-related disease. ClinVar contains an entry for this variant (Variation ID: 205357). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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