X-111401108-C-T

Position:

• chrX-111401108-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001195553.2(DCX):​c.587G>A​(p.Arg196His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 111,607 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.91

Genes affected

DCX (HGNC:2714): (doublecortin) This gene encodes a member of the doublecortin family. The protein encoded by this gene is a cytoplasmic protein and contains two doublecortin domains, which bind microtubules. In the developing cortex, cortical neurons must migrate over long distances to reach the site of their final differentiation. The encoded protein appears to direct neuronal migration by regulating the organization and stability of microtubules. In addition, the encoded protein interacts with LIS1, the regulatory gamma subunit of platelet activating factor acetylhydrolase, and this interaction is important to proper microtubule function in the developing cortex. Mutations in this gene cause abnormal migration of neurons during development and disrupt the layering of the cortex, leading to epilepsy, cognitive disability, subcortical band heterotopia ("double cortex" syndrome) in females and lissencephaly ("smooth brain" syndrome) in males. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant X-111401108-C-T is Pathogenic according to our data. Variant chrX-111401108-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-111401108-C-T is described in UniProt as null. Variant chrX-111401108-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCX	NM_001195553.2	c.587G>A	p.Arg196His	missense_variant	3/7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.587G>A	p.Arg196His	missense_variant	3/7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.587G>A	p.Arg196His	missense_variant	4/8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.587G>A	p.Arg196His	missense_variant	3/7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.587G>A	p.Arg196His	missense_variant	3/7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111607 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33779

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111607 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33779

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000166

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly type 1 due to doublecortin gene mutation Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 24, 2001	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2023	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) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

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. -

Ectopic tissue Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Subcortical laminar heterotopia, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 24, 2001

- -

Abnormal cerebral morphology Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	.;T;.;.;T;T;.;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;.;.;D;D;.;.;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	.;.;.;D;.;D;D;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;.;.;D;.;D;D;.;.
Sift4G	Uncertain	0.0070	.;.;.;D;.;D;D;.;.
Vest4		0.90, 0.90, 0.89
MVP		1.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56030372; hg19: chrX-110644336; COSMIC: COSV57566600; COSMIC: COSV57566600;