NM_001195553.2(DCX):c.226C>T (p.Arg76Cys) AND Lissencephaly type 1 due to doublecortin gene mutation

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002470773.1

Allele description [Variation Report for NM_001195553.2(DCX):c.226C>T (p.Arg76Cys)]

NM_001195553.2(DCX):c.226C>T (p.Arg76Cys)

Gene:

DCX:doublecortin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq23

Genomic location:

Preferred name:

NM_001195553.2(DCX):c.226C>T (p.Arg76Cys)

HGVS:

NC_000023.11:g.111410173G>A
NG_011750.1:g.7006C>T
NM_000555.3:c.469C>T
NM_001195553.2:c.226C>TMANE SELECT
NM_001369370.1:c.226C>T
NM_001369371.1:c.226C>T
NM_001369372.1:c.226C>T
NM_001369373.1:c.226C>T
NM_001369374.1:c.226C>T
NM_178151.3:c.226C>T
NM_178152.3:c.226C>T
NM_178153.3:c.226C>T
NP_000546.2:p.Arg157Cys
NP_001182482.1:p.Arg76Cys
NP_001356299.1:p.Arg76Cys
NP_001356300.1:p.Arg76Cys
NP_001356301.1:p.Arg76Cys
NP_001356302.1:p.Arg76Cys
NP_001356303.1:p.Arg76Cys
NP_835364.1:p.Arg76Cys
NP_835364.1:p.Arg76Cys
NP_835365.1:p.Arg76Cys
NP_835366.1:p.Arg76Cys
NC_000023.10:g.110653401G>A
NM_001195553.1:c.226C>T
NM_178151.2:c.226C>T

Protein change:

R157C

Links:

dbSNP: rs587783534

NCBI 1000 Genomes Browser:

rs587783534

Molecular consequence:

NM_000555.3:c.469C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195553.2:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369370.1:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369371.1:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369372.1:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369373.1:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369374.1:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_178151.3:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_178152.3:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_178153.3:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Lissencephaly type 1 due to doublecortin gene mutation
Synonyms:: LISSENCEPHALY, X-LINKED, 1; Lissencephaly and agenesis of corpus callosum
Identifiers:: MONDO: MONDO:0010239; MedGen: C4551968; Orphanet: 2148; OMIM: 300067

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002766939	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12838518, 18685874, 23365099, 30979500, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002766939

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 2, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations.

Guerrini R, Moro F, Andermann E, Hughes E, D'Agostino D, Carrozzo R, Bernasconi A, Flinter F, Parmeggiani L, Volzone A, Parrini E, Mei D, Jarosz JM, Morris RG, Pratt P, Tortorella G, Dubeau F, Andermann F, Dobyns WB, Das S.

Ann Neurol. 2003 Jul;54(1):30-7.

PubMed [citation]

PMID:: 12838518

The location of DCX mutations predicts malformation severity in X-linked lissencephaly.

Leger PL, Souville I, Boddaert N, Elie C, Pinard JM, Plouin P, Moutard ML, des Portes V, Van Esch H, Joriot S, Renard JL, Chelly J, Francis F, Beldjord C, Bahi-Buisson N.

Neurogenetics. 2008 Oct;9(4):277-85. doi: 10.1007/s10048-008-0141-5. Epub 2008 Aug 7.

PubMed [citation]

PMID:: 18685874

See all PubMed Citations (5)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766939.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with lissencephaly (MIM#300067) and subcortical band heterotopia (MIM#300067). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity in females diagnosed with subcortical band heterotopia (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes, 0 hemizygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 30979500). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The alternative changes to glycine, serine and proline have been reported in males with lissencephaly/subcortical band heterotopia, and females with subcortical band heterotopia (ClinVar, PMID: 12838518, 18685874, 23365099). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an individual. This variant has been reported as likely pathogenic once in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

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