NM_001195553.2(DCX):c.667G>A (p.Gly223Arg) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 5, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000996004.27

Allele description [Variation Report for NM_001195553.2(DCX):c.667G>A (p.Gly223Arg)]

NM_001195553.2(DCX):c.667G>A (p.Gly223Arg)

Gene:

DCX:doublecortin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq23

Genomic location:

Preferred name:

NM_001195553.2(DCX):c.667G>A (p.Gly223Arg)

HGVS:

NC_000023.11:g.111401028C>T
NG_011750.1:g.16151G>A
NM_000555.3:c.910G>A
NM_001195553.2:c.667G>AMANE SELECT
NM_001369370.1:c.667G>A
NM_001369371.1:c.667G>A
NM_001369372.1:c.667G>A
NM_001369373.1:c.667G>A
NM_001369374.1:c.667G>A
NM_178151.3:c.667G>A
NM_178152.3:c.667G>A
NM_178153.2:c.667G>A
NM_178153.3:c.667G>A
NP_000546.2:p.Gly304Arg
NP_001182482.1:p.Gly223Arg
NP_001356299.1:p.Gly223Arg
NP_001356300.1:p.Gly223Arg
NP_001356301.1:p.Gly223Arg
NP_001356302.1:p.Gly223Arg
NP_001356303.1:p.Gly223Arg
NP_835364.1:p.Gly223Arg
NP_835364.1:p.Gly223Arg
NP_835365.1:p.Gly223Arg
NP_835366.1:p.Gly223Arg
NC_000023.10:g.110644256C>T
NM_178151.2:c.667G>A

Protein change:

G223R

Links:

dbSNP: rs587783577

NCBI 1000 Genomes Browser:

rs587783577

Molecular consequence:

NM_000555.3:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195553.2:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369370.1:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369371.1:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369372.1:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369373.1:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369374.1:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_178151.3:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_178152.3:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_178153.3:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001150428	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (May 1, 2019)	germline	clinical testing	Citation Link,
SCV004026036	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 10, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004641543	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 5, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 31069529, 32570172, 34145886, 9618162, 11175293, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001150428

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Uncertain significance
(May 1, 2019)

germline

clinical testing

Citation Link,

SCV004026036

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 10, 2022)

de novo

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004641543

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 5, 2023)

germline

clinical testing

PubMed (6)
[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	1	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients.

Ganapathy A, Mishra A, Soni MR, Kumar P, Sadagopan M, Kanthi AV, Patric IRP, George S, Sridharan A, Thyagarajan TC, Aswathy SL, Vidya HK, Chinnappa SM, Nayanala S, Prakash MB, Raghavendrachar VG, Parulekar M, Gowda VK, Nampoothiri S, Menon RN, Pachat D, Udani V, et al.

J Neurol. 2019 Aug;266(8):1919-1926. doi: 10.1007/s00415-019-09358-1. Epub 2019 May 8.

PubMed [citation]

PMID:: 31069529

See all PubMed Citations (7)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001150428.27

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	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		1	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV004026036.1

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

Description

PS1, PS2, PM1, PM2_SUP

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004641543.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 223 of the DCX protein (p.Gly223Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with lissencephaly and subcortical band heterotopia (PMID: 31069529, 32570172, 34145886). In at least one individual the variant was observed to be de novo. This variant is also known as c.910G>A, p.Gly304Arg . ClinVar contains an entry for this variant (Variation ID: 158496). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DCX protein function with a positive predictive value of 80%. This variant disrupts the p.Gly223 amino acid residue in DCX. Other variant(s) that disrupt this residue have been observed in individuals with DCX-related conditions (PMID: 9618162, 11175293), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 20, 2024

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