ClinVar Miner

Submissions for variant NM_001195553.2(DCX):c.587G>A (p.Arg196His)

gnomAD frequency: 0.00001  dbSNP: rs56030372
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000145869 SCV000193006 pathogenic Ectopic tissue 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV001552573 SCV001773280 pathogenic not provided 2023-08-25 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18685874, 12692530, 11175293, 25868952, 11468322, 23365099, 35213059)
Invitae RCV001552573 SCV002131577 pathogenic not provided 2021-07-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg196 amino acid residue in DCX. Other variant(s) that disrupt this residue have been observed in individuals with DCX-related conditions (PMID: 18685874), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 11609). This variant has been observed in individuals with lissencephaly (PMID: 11468322, 18685874). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 196 of the DCX protein (p.Arg196His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.
Ambry Genetics RCV002512983 SCV003623699 pathogenic Inborn genetic diseases 2022-06-09 criteria provided, single submitter clinical testing The c.587G>A (p.R196H) alteration is located in exon 3 (coding exon 2) of the DCX gene. This alteration results from a G to A substitution at nucleotide position 587, causing the arginine (R) at amino acid position 196 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in multiple individuals with DCX-related lissencephaly (Matsumoto, 2001; Demelas, 2001; Leger, 2008; Bahi-Buisson, 2013; Lin, 2022). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional assays show impaired microtubule growth in a human cell line compared to controls (Lin, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf RCV000012373 SCV004046725 pathogenic Lissencephaly type 1 due to doublecortin gene mutation criteria provided, single submitter not provided
OMIM RCV000012373 SCV000032607 pathogenic Lissencephaly type 1 due to doublecortin gene mutation 2001-07-24 no assertion criteria provided literature only
OMIM RCV000012374 SCV000032608 pathogenic Subcortical laminar heterotopia, X-linked 2001-07-24 no assertion criteria provided literature only
Diagnostic Laboratory, Strasbourg University Hospital RCV002274878 SCV002562784 uncertain significance Abnormal cerebral morphology no assertion criteria provided clinical testing

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