VCV000655122.39 - ClinVar

NM_020631.6(PLEKHG5):c.2575C>T (p.Arg859Cys)

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.

(8)

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.

Uncertain significance

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.2575C>T (p.Arg859Cys)

Variation ID: 655122 Accession: VCV000655122.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.31 1: 6468261 (GRCh38) [ NCBI UCSC ] 1: 6528321 (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	Aug 14, 2019	Oct 20, 2024	May 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020631.6:c.2575C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065682.2:p.Arg859Cys	missense
NM_001042663.3:c.2686C>T	NP_001036128.2:p.Arg896Cys	missense
NM_001042664.2:c.2575C>T	NP_001036129.1:p.Arg859Cys	missense
NM_001042665.2:c.2575C>T	NP_001036130.1:p.Arg859Cys	missense
NM_001265592.2:c.2686C>T	NP_001252521.2:p.Arg896Cys	missense
NM_001265593.2:c.2782C>T	NP_001252522.1:p.Arg928Cys	missense
NM_001265594.3:c.2575C>T	NP_001252523.1:p.Arg859Cys	missense
NM_198681.4:c.2575C>T	NP_941374.3:p.Arg859Cys	missense
NC_000001.11:g.6468261G>A
NC_000001.10:g.6528321G>A
NG_007978.1:g.56749C>T
NG_029910.1:g.2935C>T
LRG_262:g.56749C>T
LRG_262t1:c.2575C>T	LRG_262p1:p.Arg859Cys

... more HGVS ... less HGVS

Protein change

R859C, R928C, R896C

Other names

Canonical SPDI

NC_000001.11:6468260:G: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.

0.00020 (A)

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

The Genome Aggregation Database (gnomAD) 0.00019

1000 Genomes Project 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

The Genome Aggregation Database (gnomAD), exomes 0.00023

Trans-Omics for Precision Medicine (TOPMed) 0.00023

1000 Genomes Project 30x 0.00031

Exome Aggregation Consortium (ExAC) 0.00032

Links

dbSNP: rs150666859 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	1325	1436

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	Uncertain significance (1)	criteria provided, single submitter	Jul 12, 2022	RCV000811234.7
Neuronopathy, distal hereditary motor, autosomal recessive 4	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001101746.5
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	May 31, 2024	RCV001530980.27
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jan 9, 2023	RCV002453833.3
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 31, 2024	RCV003987710.1
PLEKHG5-related disorder	Uncertain significance (1)	no assertion criteria provided	Jun 27, 2024	RCV004754570.1

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.
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001258383.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jul 12, 2022)	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 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000951491.5 First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 859 of the PLEKHG5 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 859 of the PLEKHG5 protein (p.Arg859Cys). This variant is present in population databases (rs150666859, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 655122). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jan 31, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004804070.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Comment: Variant summary: PLEKHG5 c.2575C>T (p.Arg859Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more) Variant summary: PLEKHG5 c.2575C>T (p.Arg859Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 240396 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLEKHG5 causing Distal Spinal Muscular Atrophy, Autosomal Recessive 4 (0.00023 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2575C>T in individuals affected with Distal Spinal Muscular Atrophy, Autosomal Recessive 4 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 655122). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Jan 09, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002739565.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.2575C>T (p.R859C) alteration is located in exon 20 (coding exon 19) of the PLEKHG5 gene. This alteration results from a C to T substitution … (more) The c.2575C>T (p.R859C) alteration is located in exon 20 (coding exon 19) of the PLEKHG5 gene. This alteration results from a C to T substitution at nucleotide position 2575, causing the arginine (R) at amino acid position 859 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005187125.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024
Uncertain significance (May 31, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001812966.4 First in ClinVar: Sep 08, 2021 Last updated: Sep 16, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Apr 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001745901.20 First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Jun 27, 2024)	no assertion criteria provided Method: clinical testing	PLEKHG5-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005353005.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PLEKHG5 c.2575C>T variant is predicted to result in the amino acid substitution p.Arg859Cys. To our knowledge, this variant has not been reported in the … (more) The PLEKHG5 c.2575C>T variant is predicted to result in the amino acid substitution p.Arg859Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 859 of the PLEKHG5 protein (p.Arg859Cys). This variant is present in population databases (rs150666859, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 655122). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Variant summary: PLEKHG5 c.2575C>T (p.Arg859Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 240396 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLEKHG5 causing Distal Spinal Muscular Atrophy, Autosomal Recessive 4 (0.00023 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2575C>T in individuals affected with Distal Spinal Muscular Atrophy, Autosomal Recessive 4 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 655122). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

The c.2575C>T (p.R859C) alteration is located in exon 20 (coding exon 19) of the PLEKHG5 gene. This alteration results from a C to T substitution at nucleotide position 2575, causing the arginine (R) at amino acid position 859 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

The PLEKHG5 c.2575C>T variant is predicted to result in the amino acid substitution p.Arg859Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs150666859 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_020631.6(PLEKHG5):c.2575C>T (p.Arg859Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150666859 ...