VCV000522394.13 - ClinVar

NM_022835.3(PLEKHG2):c.610C>T (p.Arg204Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(4); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022835.3(PLEKHG2):c.610C>T (p.Arg204Trp)

Variation ID: 522394 Accession: VCV000522394.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 39416866 (GRCh38) [ NCBI UCSC ] 19: 39907506 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 22, 2018	Oct 8, 2024	Nov 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_022835.3:c.610C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_073746.2:p.Arg204Trp	missense
NM_001351693.2:c.433C>T	NP_001338622.1:p.Arg145Trp	missense
NM_001351694.2:c.610C>T	NP_001338623.1:p.Arg204Trp	missense
NC_000019.10:g.39416866C>T
NC_000019.9:g.39907506C>T
NG_054904.1:g.9285C>T

... more HGVS ... less HGVS

Protein change

R204W, R145W

Other names

PLEKHG2, ARG204TRP (rs201201843)

Canonical SPDI

NC_000019.10:39416865:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Exome Aggregation Consortium (ExAC) 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00036

The Genome Aggregation Database (gnomAD) 0.00039

Links

ClinGen: CA9429190 OMIM: 611893.0001 dbSNP: rs201201843 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PLEKHG2		-	-	GRCh38 GRCh37	465	478

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Leukodystrophy and acquired microcephaly with or without dystonia;	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 31, 2023	RCV000625530.7
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Nov 27, 2023	RCV001868155.4
PLEKHG2-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Apr 20, 2023	RCV003392458.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Aug 12, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy and acquired microcephaly with or without dystonia; (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556727.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022	Publications: PubMed (1) PubMed: 26573021 Comment: The PLEKHG2 c.610C>T missense variant is classified as Likely Pathogenic (PP1_moderate, PS3_moderate, PS4_moderate) The PLEKHG2 c.610C>T missense variant is a single nucleotide change in exon … (more) The PLEKHG2 c.610C>T missense variant is classified as Likely Pathogenic (PP1_moderate, PS3_moderate, PS4_moderate) The PLEKHG2 c.610C>T missense variant is a single nucleotide change in exon 7 of the PLEKHG2 gene, which is predicted to change the amino acid arginine at position 204 in the protein to tryptophan. This variant has been reported in a homozygous state in five patients with profound mental retardation, dystonia, postnatal microcephaly, and common brain MRI findings, from two unrelated consanguinous families (PS4_moderate). This variant cosegregated with disease and heterozyous carriers of this variant were unaffected (PMID:26573021) (PP1_moderate). Functional studies demonstrate decreased basal and stimulated RhoGEF activity of the R204 mutant compared with wildtype in luciferase assays, suggesting the R204 variant impairs the ability of the PLEKHG2 catalytic domain to form an active conformation (PMID:26573021) (PS3_moderate). This variant has been reported in dbSNP (rs20101843) and has been reported in population databases (gnomAD = 0.035%, 96 of 272616 sequenced alleles, no homozygotes). This variant has been reported in ClinVar as pathogenic for Leukodystrophy and aquired microcephaly with or without dystonia (Variation ID: VCV000522394.1). It has also been reported as damaging in HGMD for mental retardation, dystonia and postnatal microcephaly (CM1617668). Computational predictions are equivocal. (less)
Likely pathogenic (Jun 27, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Leukodystrophy and acquired microcephaly with or without dystonia; Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004021197.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (1) PubMed: 26573021 Comment: Variant summary: PLEKHG2 c.610C>T (p.Arg204Trp) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. … (more) Variant summary: PLEKHG2 c.610C>T (p.Arg204Trp) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 241264 control chromosomes (gnomAD). c.610C>T has been reported in the literature in two unrelated consanguineous families (in homozygous state) affected with Microcephaly-dystonia (example: Edvardson_2016). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function suggests this variant can impair normal protein function (example: Edvardson_2016). The following publication has been ascertained in the context of this evaluation (PMID: 26573021). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (Aug 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy and acquired microcephaly with or without dystonia; (Autosomal recessive inheritance) Affected status: no Allele origin: unknown	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center Accession: SCV004031107.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023
Likely pathogenic (Apr 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PLEKHG2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120466.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The PLEKHG2 c.610C>T variant is predicted to result in the amino acid substitution p.Arg204Trp. This variant has been reported in the homozygous state in multiple … (more) The PLEKHG2 c.610C>T variant is predicted to result in the amino acid substitution p.Arg204Trp. This variant has been reported in the homozygous state in multiple individuals among two families with profound intellectual disability, dystonia, postnatal microcephaly, and distinct neuroimaging profiles (Edvardson et al. 2016. PubMed ID: 26573021). This variant is reported in 0.15% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39907506-C-T). This variant is interpreted as likely pathogenic. (less)
Likely pathogenic (Nov 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002261936.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 26573021 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 204 of the PLEKHG2 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 204 of the PLEKHG2 protein (p.Arg204Trp). This variant is present in population databases (rs201201843, gnomAD 0.1%). This missense change has been observed in individuals with acquired microcephaly with or without dystonia (PMID: 26573021). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 522394). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PLEKHG2 function (PMID: 26573021). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Uncertain significance (Sep 30, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325911.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Published functional studies suggest R204W impairs catalytic activity and causes defects in dendritic spine morphology formation (Edvardson et al., 2016; Nishikawa et al., 2022); Reported … (more) Published functional studies suggest R204W impairs catalytic activity and causes defects in dendritic spine morphology formation (Edvardson et al., 2016; Nishikawa et al., 2022); Reported in multiple individuals from two unrelated families with severe developmental delay, postnatal microcephaly, hypotonia, leukodystrophy, variable presence of dystonia, and seizures (Edvardson et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 34426522, 35203342, 26573021) (less)
Pathogenic (Sep 30, 2024)	no assertion criteria provided Method: literature only	LEUKODYSTROPHY AND ACQUIRED MICROCEPHALY WITH OR WITHOUT DYSTONIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000746025.2 First in ClinVar: Apr 22, 2018 Last updated: Oct 08, 2024	Publications: PubMed (2) PubMed: 26573021‚ 35203342 Comment on evidence: In 5 children from 2 unrelated consanguineous Palestinian families with leukodystrophy and acquired microcephaly with or without dystonia (LDAMD; 616763), Edvardson et al. (2016) identified … (more) In 5 children from 2 unrelated consanguineous Palestinian families with leukodystrophy and acquired microcephaly with or without dystonia (LDAMD; 616763), Edvardson et al. (2016) identified a homozygous c.610C-T transition (rs201201843) in the PLEKHG2 gene, resulting in an arg204-to-trp (R204W) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing and segregated with the disorder in both families. It was found in only 1 of 6,437 exomes in the Exome Variant Server database (May 25, 2014). Haplotype analysis indicated a founder effect between the 2 families. In vitro functional expression studies in HEK293 cells showed that the mutant protein was expressed normally, but had decreased basal and stimulated catalytic activity compared to wildtype. Patient cells showed impaired stimulated actin polymerization compared to controls. Knockdown of PLEKHG2 in control cells also resulted in decreased stimulated actin polymerization, indicating that the R204W mutation resulted in a loss of function. Using transgenic expression in COS7 cells, Nishikawa et al. (2022) showed that mouse Plekhg2 carrying an arg200-to-trp (R200W) mutation, corresponding to the human R204W mutation, had impaired G-beta/gamma-stimulated catalytic activity on Rac (602048) and Cdc42 (116952) in vitro. Knockdown analysis in mouse embryos revealed that silencing Plekhg2 expression delayed dendritic arbor formation in vivo. This phenotype was rescued by expressing wildtype Plekhg2, but not by expressing the Plekhg2 R200W mutant. Plekhg2 knockdown also impaired axon pathfinding of cortical neurons and caused defects in dendritic spine morphology formation. (less)

Comment:

The PLEKHG2 c.610C>T missense variant is classified as Likely Pathogenic (PP1_moderate, PS3_moderate, PS4_moderate) The PLEKHG2 c.610C>T missense variant is a single nucleotide change in exon 7 of the PLEKHG2 gene, which is predicted to change the amino acid arginine at position 204 in the protein to tryptophan. This variant has been reported in a homozygous state in five patients with profound mental retardation, dystonia, postnatal microcephaly, and common brain MRI findings, from two unrelated consanguinous families (PS4_moderate). This variant cosegregated with disease and heterozyous carriers of this variant were unaffected (PMID:26573021) (PP1_moderate). Functional studies demonstrate decreased basal and stimulated RhoGEF activity of the R204 mutant compared with wildtype in luciferase assays, suggesting the R204 variant impairs the ability of the PLEKHG2 catalytic domain to form an active conformation (PMID:26573021) (PS3_moderate). This variant has been reported in dbSNP (rs20101843) and has been reported in population databases (gnomAD = 0.035%, 96 of 272616 sequenced alleles, no homozygotes). This variant has been reported in ClinVar as pathogenic for Leukodystrophy and aquired microcephaly with or without dystonia (Variation ID: VCV000522394.1). It has also been reported as damaging in HGMD for mental retardation, dystonia and postnatal microcephaly (CM1617668). Computational predictions are equivocal.

Comment:

Variant summary: PLEKHG2 c.610C>T (p.Arg204Trp) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 241264 control chromosomes (gnomAD). c.610C>T has been reported in the literature in two unrelated consanguineous families (in homozygous state) affected with Microcephaly-dystonia (example: Edvardson_2016). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function suggests this variant can impair normal protein function (example: Edvardson_2016). The following publication has been ascertained in the context of this evaluation (PMID: 26573021). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

The PLEKHG2 c.610C>T variant is predicted to result in the amino acid substitution p.Arg204Trp. This variant has been reported in the homozygous state in multiple individuals among two families with profound intellectual disability, dystonia, postnatal microcephaly, and distinct neuroimaging profiles (Edvardson et al. 2016. PubMed ID: 26573021). This variant is reported in 0.15% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39907506-C-T). This variant is interpreted as likely pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 204 of the PLEKHG2 protein (p.Arg204Trp). This variant is present in population databases (rs201201843, gnomAD 0.1%). This missense change has been observed in individuals with acquired microcephaly with or without dystonia (PMID: 26573021). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 522394). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PLEKHG2 function (PMID: 26573021). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

Published functional studies suggest R204W impairs catalytic activity and causes defects in dendritic spine morphology formation (Edvardson et al., 2016; Nishikawa et al., 2022); Reported in multiple individuals from two unrelated families with severe developmental delay, postnatal microcephaly, hypotonia, leukodystrophy, variable presence of dystonia, and seizures (Edvardson et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 34426522, 35203342, 26573021)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes.	Nishikawa M	Cells	2022	PMID: 35203342
Microcephaly-dystonia due to mutated PLEKHG2 with impaired actin polymerization.	Edvardson S	Neurogenetics	2016	PMID: 26573021

Text-mined citations for rs201201843 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_022835.3(PLEKHG2):c.610C>T (p.Arg204Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201201843 ...