ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.958G>A (p.Asp320Asn) (rs150613209)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000145921 SCV000193058 benign not specified 2013-02-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000280887 SCV000410357 benign Myopathy, centronuclear, 1 2018-01-12 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000802315 SCV000410358 benign Charcot-Marie-Tooth disease, dominant intermediate B 2018-01-12 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx RCV000145921 SCV000726425 likely benign not specified 2018-01-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756033 SCV000883738 uncertain significance not provided 2017-06-14 criteria provided, single submitter clinical testing The p.Asp320Asn variant (rs150613209) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database (Variation ID: 158529). This variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.01% (identified in 33 out of 276,996 chromosomes). The aspartic acid at codon 320 is moderately conserved considering 14 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on DNM2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing). Therefore, based on the available information, the clinical significance of the p.Asp320Asn variant cannot be determined with certainty.
Invitae RCV000802315 SCV000942140 uncertain significance Charcot-Marie-Tooth disease, dominant intermediate B 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 320 of the DNM2 protein (p.Asp320Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs150613209, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DNM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 158529). 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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