rs587783559

Variant names:

• chrX-111401162-C-A
• rs587783559
• NM_001195553.2:c.533G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-111401162-C-A
• chrX-111401162-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001195553.2(DCX):​c.533G>T​(p.Arg178Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R178C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.17

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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-111401163-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant X-111401162-C-A is Pathogenic according to our data. Variant chrX-111401162-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158473.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}. Variant chrX-111401162-C-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2	c.533G>T	p.Arg178Leu	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.533G>T	p.Arg178Leu	missense_variant	Exon 3 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.533G>T	p.Arg178Leu	missense_variant	Exon 4 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.533G>T	p.Arg178Leu	missense_variant	Exon 3 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.533G>T	p.Arg178Leu	missense_variant	Exon 3 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Sep 03, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant impairs cooperative microtubule binding (PMID: 22727374); 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: 22857951, 9489700, 19416314, 22727374, 25283777, 9989615, 12838518, 23365099) -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 178 of the DCX protein (p.Arg178Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of X-linked dominant DCX-related conditions (PMID: 9489700). It has also been observed to segregate with disease in related individuals. This variant is also known as R59L. ClinVar contains an entry for this variant (Variation ID: 158473). 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 not expected to disrupt DCX protein function with a negative predictive value of 80%. This variant disrupts the p.Arg178 amino acid residue in DCX. Other variant(s) that disrupt this residue have been observed in individuals with DCX-related conditions (PMID: 12390976), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Lissencephaly type 1 due to doublecortin gene mutation Pathogenic:1

Apr 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DCX c.533G>T (p.Arg178Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182903 control chromosomes. c.533G>T has been observed in a family in which a mother and 2 of her daughters had clinical features of X-linked dominant DCX-related conditions and the variant was shown to segregate with disease (example: Gleeson_1998). These data indicate that the variant may be associated with disease. At-least two publications report experimental evidence evaluating an impact on protein function. Specifically, it was demonstrated that the variant weakens the cooperative microtubule binding and is associated with significantly reduced DCX-microtubule binding compared to wild-type (example: Bechstedt_2012, Dema_2024). The following publications have been ascertained in the context of this evaluation (PMID: 22727374, 39626666, 9489700). ClinVar contains an entry for this variant (Variation ID: 158473). Based on the evidence outlined above, the variant was classified as likely 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	.;T;.;.;T;T;.;T;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	.;.;.;T;T;.;.;T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.0	.;.;.;D;.;D;D;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.011	.;.;.;D;.;D;D;.;.
Sift4G	Uncertain	0.012	.;.;.;D;.;D;D;.;.
Vest4		0.91, 0.89, 0.89
MVP		1.0
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.90
gMVP		0.97

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: rs587783559; hg19: chrX-110644390;