rs104894780

Variant names:

• chrX-111401121-G-A
• rs104894780
• NM_001195553.2:c.574C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-111401121-G-A
• chrX-111401121-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001195553.2(DCX):​c.574C>T​(p.Arg192Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R192Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.82
• Publications: 5 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 12 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
• 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, 0.923
• PP5: Variant X-111401121-G-A is Pathogenic according to our data. Variant chrX-111401121-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11598.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	c.574C>T	p.Arg192Trp	missense_variant	Exon 3 of 7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.574C>T	p.Arg192Trp	missense_variant	Exon 3 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.574C>T	p.Arg192Trp	missense_variant	Exon 4 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.574C>T	p.Arg192Trp	missense_variant	Exon 3 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.574C>T	p.Arg192Trp	missense_variant	Exon 3 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 13, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect and show that this variant impairs the interaction of the DCX gene with microtubules and leads to defects in cortical neuronal migration (Taylor et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11175293, 10749977, 11001923, 19416314, 18685874, 12692530, 25868952, 12820024, 15607950, 9489700, 15045646, 9489699, 10946000, 23365099) -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 192 of the DCX protein (p.Arg192Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of DCX-related conditions (PMID: 9489699, 9489700, 9618162, 11175293, 17111359, 18685874; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11598). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DCX protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Lissencephaly type 1 due to doublecortin gene mutation Pathogenic:1

Jan 09, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jan 09, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	.;T;.;.;T;T;.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;.;.;D;D;.;.;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
PhyloP100		5.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.0	.;.;.;D;.;D;D;.;.
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	.;.;.;D;.;D;D;.;.
Sift4G	Uncertain	0.057	.;.;.;T;.;T;T;.;.
Vest4		0.83, 0.85
MVP		1.0
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.93
gMVP		0.97
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894780; hg19: chrX-110644349;