VCV002942080.3 - ClinVar

NM_020631.6(PLEKHG5):c.1542+1G>C

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Likely pathogenic
Likely pathogenic (1)

This classification is based on the single submission received

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020631.6(PLEKHG5):c.1542+1G>C

Variation ID: 2942080 Accession: VCV002942080.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.31 1: 6470734 (GRCh38) [ NCBI UCSC ] 1: 6530794 (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	Feb 29, 2024	Feb 23, 2026	Jan 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020631.6:c.1542+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001042663.3:c.1653+1G>C		splice donor
NM_001042664.2:c.1542+1G>C		splice donor
NM_001042665.2:c.1542+1G>C		splice donor
NM_001265592.2:c.1653+1G>C		splice donor
NM_001265593.2:c.1749+1G>C		splice donor
NM_001265594.3:c.1542+1G>C		splice donor
NM_198681.4:c.1542+1G>C		splice donor
NC_000001.11:g.6470734C>G
NC_000001.10:g.6530794C>G
NG_007978.1:g.54276G>C
NG_029910.1:g.462G>C
LRG_262:g.54276G>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:6470733:C:G

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA338126223 dbSNP: rs1644545351 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.
PLEKHG5		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1477	1597

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.
Charcot-Marie-Tooth disease recessive intermediate C Neuronopathy, distal hereditary motor, autosomal recessive 4	Likely pathogenic (1)	criteria provided, single submitter	Jan 16, 2023	RCV003805294.4

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.	Expand all rows Collapse all rows 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 (Jan 16, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Neuronopathy, distal hereditary motor, autosomal recessive 4 Charcot-Marie-Tooth disease recessive intermediate C Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004593055.3 First in ClinVar: Feb 28, 2024 Last updated: Feb 23, 2026	Publications: PubMed (3) PubMed: 16199547‚ 17564964‚ 23777631 Comment: show This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 14 of the PLEKHG5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PLEKHG5 are known to be pathogenic (PMID: 17564964, 23777631). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 14 of the PLEKHG5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PLEKHG5 are known to be pathogenic (PMID: 17564964, 23777631).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.	Azzedine H	Human molecular genetics	2013	PMID: 23777631
The nuclear factor kappaB-activator gene PLEKHG5 is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset.	Maystadt I	American journal of human genetics	2007	PMID: 17564964
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs1644545351 ...

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 Apr 13, 2026