VCV001788740.3 - ClinVar

NM_020631.6(PLEKHG5):c.2269G>T (p.Glu757Ter)

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.

(2)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020631.6(PLEKHG5):c.2269G>T (p.Glu757Ter)

Variation ID: 1788740 Accession: VCV001788740.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.31 1: 6468567 (GRCh38) [ NCBI UCSC ] 1: 6528627 (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	Nov 29, 2022	May 1, 2024	Jun 9, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020631.6:c.2269G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065682.2:p.Glu757Ter	nonsense
NM_001042663.3:c.2380G>T	NP_001036128.2:p.Glu794Ter	nonsense
NM_001042664.2:c.2269G>T	NP_001036129.1:p.Glu757Ter	nonsense
NM_001042665.2:c.2269G>T	NP_001036130.1:p.Glu757Ter	nonsense
NM_001265592.2:c.2380G>T	NP_001252521.2:p.Glu794Ter	nonsense
NM_001265593.2:c.2476G>T	NP_001252522.1:p.Glu826Ter	nonsense
NM_001265594.3:c.2269G>T	NP_001252523.1:p.Glu757Ter	nonsense
NM_198681.4:c.2269G>T	NP_941374.3:p.Glu757Ter	nonsense
NC_000001.11:g.6468567C>A
NC_000001.10:g.6528627C>A
NG_007978.1:g.56443G>T
NG_029910.1:g.2629G>T
LRG_262:g.56443G>T
LRG_262t1:c.2269G>T	LRG_262p1:p.Glu757Ter

... more HGVS ... less HGVS

Protein change

E794*, E757*, E826*

Other names

Canonical SPDI

NC_000001.11:6468566:C:A

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.

Links

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		-	-	GRCh38 GRCh37	1327	1438

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.
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Sep 26, 2022	RCV002443849.2
Charcot-Marie-Tooth disease recessive intermediate C Neuronopathy, distal hereditary motor, autosomal recessive 4	Pathogenic (1)	criteria provided, single submitter	Jun 9, 2023	RCV003775165.2

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.
Pathogenic (Jun 09, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004574569.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 17564964‚ 23777631 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1788740). This variant has not been … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1788740). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Glu757*) in the PLEKHG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLEKHG5 are known to be pathogenic (PMID: 17564964, 23777631). (less)
Pathogenic (Sep 26, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002733252.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.E757* pathogenic mutation (also known as c.2269G>T), located in coding exon 19 of the PLEKHG5 gene, results from a G to T substitution at … (more) The p.E757* pathogenic mutation (also known as c.2269G>T), located in coding exon 19 of the PLEKHG5 gene, results from a G to T substitution at nucleotide position 2269. This changes the amino acid from a glutamic acid to a stop codon within coding exon 19. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1788740). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Glu757*) in the PLEKHG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLEKHG5 are known to be pathogenic (PMID: 17564964, 23777631).

Comment:

The p.E757* pathogenic mutation (also known as c.2269G>T), located in coding exon 19 of the PLEKHG5 gene, results from a G to T substitution at nucleotide position 2269. This changes the amino acid from a glutamic acid to a stop codon within coding exon 19. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
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

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_020631.6(PLEKHG5):c.2269G>T (p.Glu757Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...