NM_020631.6(PLEKHG5):c.1396del (p.Ala466fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 13, 2023
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:: RCV003804355.1

Allele description [Variation Report for NM_020631.6(PLEKHG5):c.1396del (p.Ala466fs)]

NM_020631.6(PLEKHG5):c.1396del (p.Ala466fs)

Gene:

PLEKHG5:pleckstrin homology and RhoGEF domain containing G5 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1p36.31

Genomic location:

Preferred name:

NM_020631.6(PLEKHG5):c.1396del (p.Ala466fs)

HGVS:

NC_000001.11:g.6470883del
NG_007978.1:g.54129del
NG_029910.1:g.315del
NM_001042663.3:c.1507del
NM_001042664.2:c.1396del
NM_001042665.2:c.1396del
NM_001265592.2:c.1507del
NM_001265593.2:c.1603del
NM_001265594.3:c.1396del
NM_020631.6:c.1396delMANE SELECT
NM_198681.4:c.1396del
NP_001036128.2:p.Ala503fs
NP_001036129.1:p.Ala466fs
NP_001036130.1:p.Ala466fs
NP_001252521.2:p.Ala503fs
NP_001252522.1:p.Ala535fs
NP_001252523.1:p.Ala466fs
NP_065682.2:p.Ala466Argfs
NP_065682.2:p.Ala466fs
NP_941374.3:p.Ala466fs
LRG_262t1:c.1394del
LRG_262:g.54129del
LRG_262p1:p.Ala466Argfs
NC_000001.10:g.6530941del
NC_000001.10:g.6530943del
NM_020631.3:c.1394delG

Protein change:

A466fs

Molecular consequence:

NM_001042663.3:c.1507del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001042664.2:c.1396del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001042665.2:c.1396del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001265592.2:c.1507del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001265593.2:c.1603del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001265594.3:c.1396del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_020631.6:c.1396del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_198681.4:c.1396del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Neuronopathy, distal hereditary motor, autosomal recessive 4
Synonyms:: Distal spinal muscular atrophy, autosomal recessive 4; Autosomal recessive lower motor neuron disease with childhood onset; NEUROPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 4
Identifiers:: MONDO: MONDO:0012608; MedGen: C1970211; Orphanet: 206580; OMIM: 611067

Name:: Charcot-Marie-Tooth disease recessive intermediate C
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, RECESSIVE INTERMEDIATE C
Identifiers:: MONDO: MONDO:0014154; MedGen: C3809309; Orphanet: 369867; OMIM: 615376

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004596033	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17564964, 23777631, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004596033

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 13, 2023)

germline

clinical testing

PubMed (3)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The nuclear factor kappaB-activator gene PLEKHG5 is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset.

Maystadt I, Rezsöhazy R, Barkats M, Duque S, Vannuffel P, Remacle S, Lambert B, Najimi M, Sokal E, Munnich A, Viollet L, Verellen-Dumoulin C.

Am J Hum Genet. 2007 Jul;81(1):67-76. Epub 2007 May 16.

PubMed [citation]

PMID:: 17564964
PMCID:: PMC1950913

PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.

Azzedine H, Zavadakova P, Planté-Bordeneuve V, Vaz Pato M, Pinto N, Bartesaghi L, Zenker J, Poirot O, Bernard-Marissal N, Arnaud Gouttenoire E, Cartoni R, Title A, Venturini G, Médard JJ, Makowski E, Schöls L, Claeys KG, Stendel C, Roos A, Weis J, Dubourg O, Leal Loureiro J, et al.

Hum Mol Genet. 2013 Oct 15;22(20):4224-32. doi: 10.1093/hmg/ddt274. Epub 2013 Jun 17.

PubMed [citation]

PMID:: 23777631
PMCID:: PMC3983407

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004596033.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala466Argfs*10) 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).

#	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: Mar 5, 2024

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