X-111401108-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Consequence

DCX
NM_001195553.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 7.91

Publications

11 publications found

Variant links:

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]

DCX Gene-Disease associations (from GenCC):

lissencephaly spectrum disorders
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
lissencephaly type 1 due to doublecortin gene mutation
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
subcortical band heterotopia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DCX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001195553.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-111401109-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158483.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 87 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to lissencephaly type 1 due to doublecortin gene mutation, lissencephaly spectrum disorders, subcortical band heterotopia.

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 VariationId is 11609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2 link	c.587G>A	p.Arg196His	missense_variant	Exon 3 of 7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DCX	ENST00000636035.2 link	c.587G>A	p.Arg196His	missense_variant	Exon 3 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8 link	c.587G>A	p.Arg196His	missense_variant	Exon 4 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1 link	c.587G>A	p.Arg196His	missense_variant	Exon 3 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1 link	c.587G>A	p.Arg196His	missense_variant	Exon 3 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111607

Hom.:

Cov.:

show subpopulations

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.:

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111607

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33779

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30659

American (AMR)

AF:

0.00

AC:

AN:

10470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3556

South Asian (SAS)

AF:

0.00

AC:

AN:

2630

European-Finnish (FIN)

AF:

0.000166

AC:

AN:

6033

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53188

Other (OTH)

AF:

0.00

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lissencephaly type 1 due to doublecortin gene mutation

Pathogenic:2

Institute of Human Genetics, University Hospital of Duesseldorf

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 24, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:2

Aug 25, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

Jul 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. For these reasons, this variant has been classified as Pathogenic. 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. 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with lissencephaly (PMID: 11468322, 18685874). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11609). -

Inborn genetic diseases

Pathogenic:1

Jun 09, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Ectopic tissue

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Subcortical laminar heterotopia, X-linked

Pathogenic:1

Jul 24, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Abnormal cerebral morphology

Uncertain:1

Diagnostic Laboratory, Strasbourg University Hospital

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.64

BayesDel_noAF

Pathogenic

0.68

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

.;T;.;.;T;T;.;T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;.;.;D;D;.;.;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.16

PhyloP100

7.9

PrimateAI

Pathogenic

0.92

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

GERP RS

4.7

Varity_R

0.97

gMVP

0.95

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over