rs587783590

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001195553.2(DCX):c.814C>T(p.Arg272*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,264 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

DCX
NM_001195553.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.92

Publications

4 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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-111331036-G-A is Pathogenic according to our data. Variant chrX-111331036-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 158509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195553.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DCX	NM_001195553.2	MANE Select	c.814C>T	p.Arg272*	stop_gained	Exon 5 of 7	NP_001182482.1
DCX	NM_000555.3		c.1057C>T	p.Arg353*	stop_gained	Exon 5 of 7	NP_000546.2
DCX	NM_001369370.1		c.814C>T	p.Arg272*	stop_gained	Exon 5 of 7	NP_001356299.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DCX	ENST00000636035.2	TSL:2 MANE Select	c.814C>T	p.Arg272*	stop_gained	Exon 5 of 7	ENSP00000490614.1
DCX	ENST00000358070.10	TSL:1	c.994C>T	p.Arg332*	stop_gained	Exon 5 of 7	ENSP00000350776.6
DCX	ENST00000356220.8	TSL:5	c.814C>T	p.Arg272*	stop_gained	Exon 6 of 8	ENSP00000348553.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000548

AC:

AN:

182452

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362682

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26381

American (AMR)

AF:

0.00

AC:

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19354

East Asian (EAS)

AF:

0.00

AC:

AN:

30165

South Asian (SAS)

AF:

0.00

AC:

AN:

54115

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4097

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841478

Other (OTH)

AF:

0.00

AC:

AN:

46036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000427

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 28, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 23365099, 11175293, 25868952, 10369164)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This premature translational stop signal has been observed in individual(s) with X-linked lissencephaly and subcortical band heterotopia (PMID: 10369164). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 158509). This variant is present in population databases (rs587783590, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg272*) in the DCX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCX are known to be pathogenic (PMID: 11175293, 23365099).

Lissencephaly type 1 due to doublecortin gene mutation

Pathogenic:3

Sep 16, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 09, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified as mosaic (app 30 %) Criteria applied: PVS1, PS4_MOD, PM2_SUP

Jan 10, 2025

Department of Neurology, Zibo Changguo Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2_Supporting, PS4_Supporting

Inborn genetic diseases

Pathogenic:1

Dec 03, 2018

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R272* pathogenic mutation (also known as c.814C>T), located in coding exon 4 of the DCX gene, results from a C to T substitution at nucleotide position 814. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been detected in familial and sporadic cases of subcortical band heterotopia (SBH) and seizures (Kato M et al. Hum. Genet., 1999 Apr;104:341-4; Matsumoto N et al. Eur. J. Hum. Genet., 2001 Jan;9:5-12 Bahi-Buisson N et al. Brain, 2013 Jan;136:223-44). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Ectopic tissue

Pathogenic:1

May 21, 2014

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.90

PhyloP100

2.9

Vest4

0.98

GERP RS

4.5

Mutation Taster

=0/200

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over