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

gnomAD frequency: 0.00001  dbSNP: rs56030372

Total submissions: 8

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