ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.737C>T (p.Thr246Ile) (rs374596045)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000394182 SCV000361556 uncertain significance Histiocytic medullary reticulosis 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000520038 SCV000617002 uncertain significance not provided 2016-01-07 criteria provided, single submitter clinical testing The T246I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. T246I 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000805877 SCV000945852 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 246 of the DCLRE1C protein (p.Thr246Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs374596045, ExAC 0.05%). This variant has not been reported in the literature in individuals with DCLRE1C-related disease. ClinVar contains an entry for this variant (Variation ID: 299319). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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