VCV000055907.6 - ClinVar

NM_007259.5(VPS45):c.712G>A (p.Glu238Lys)

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.

(3)

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.

Likely 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_007259.5(VPS45):c.712G>A (p.Glu238Lys)

Variation ID: 55907 Accession: VCV000055907.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q21.2 1: 150081366 (GRCh38) [ NCBI UCSC ] 1: 150053448 (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	Mar 16, 2018	Feb 14, 2024	Feb 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_007259.5:c.712G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009190.2:p.Glu238Lys	missense
NM_001279353.2:c.397G>A	NP_001266282.1:p.Glu133Lys	missense
NM_001279354.2:c.604G>A	NP_001266283.1:p.Glu202Lys	missense
NR_103998.2:n.587G>A		non-coding transcript variant
NC_000001.11:g.150081366G>A
NC_000001.10:g.150053448G>A
NG_033910.1:g.19074G>A
LRG_1170:g.19074G>A
LRG_1170t1:c.712G>A	LRG_1170p1:p.Glu238Lys
	Q9NRW7:p.Glu238Lys

... more HGVS ... less HGVS

Protein change

E238K, E133K, E202K

Other names

Canonical SPDI

NC_000001.11:150081365: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.

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

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA1073223 UniProtKB: Q9NRW7#VAR_069866 OMIM: 610035.0002 dbSNP: rs782269909 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.
VPS45		-	-	GRCh38 GRCh37	580	601

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.
Congenital neutropenia-myelofibrosis-nephromegaly syndrome	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 14, 2023	RCV000049321.9

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 (Feb 14, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Congenital neutropenia-myelofibrosis-nephromegaly syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002290553.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 23738510‚ 26358756‚ 32037586 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 238 of the VPS45 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 238 of the VPS45 protein (p.Glu238Lys). This variant is present in population databases (rs782269909, gnomAD 0.009%). This missense change has been observed in individuals with VPS45 deficiency (PMID: 23738510, 26358756, 32037586). ClinVar contains an entry for this variant (Variation ID: 55907). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VPS45 protein function. Experimental studies have shown that this missense change affects VPS45 function (PMID: 23738510). 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)
Likely pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital neutropenia-myelofibrosis-nephromegaly syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002572955.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (2) PubMed: 23738510‚ 26358756 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.44). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with VPS45-related disorder (ClinVar ID: VCV000055907 / PMID: 26358756). A different missense change at the same codon (p.Glu238Gln) has been reported to be associated with VPS45-related disorder (PMID: 23738510). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Feeding difficulties (present) , Recurrent infections (present) , Seizure (present)
Pathogenic (Jul 04, 2013)	no assertion criteria provided Method: literature only	NEUTROPENIA, SEVERE CONGENITAL, 5, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000081753.3 First in ClinVar: Jul 24, 2013 Last updated: Apr 09, 2023	Publications: PubMed (1) PubMed: 23738510 Comment on evidence: In 2 sibs, born of consanguineous Moroccan parents, with severe congenital neutropenia-5 (SCN5; 615285), Vilboux et al. (2013) identified a homozygous c.712G-A transition in the … (more) In 2 sibs, born of consanguineous Moroccan parents, with severe congenital neutropenia-5 (SCN5; 615285), Vilboux et al. (2013) identified a homozygous c.712G-A transition in the VPS45 gene, resulting in a glu238-to-lys (E238K) substitution at a highly conserved residue. These sibs also had neurologic defects, which may have been unrelated to the immunodeficiency. (less)

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 238 of the VPS45 protein (p.Glu238Lys). This variant is present in population databases (rs782269909, gnomAD 0.009%). This missense change has been observed in individuals with VPS45 deficiency (PMID: 23738510, 26358756, 32037586). ClinVar contains an entry for this variant (Variation ID: 55907). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VPS45 protein function. Experimental studies have shown that this missense change affects VPS45 function (PMID: 23738510). 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:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.44). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with VPS45-related disorder (ClinVar ID: VCV000055907 / PMID: 26358756). A different missense change at the same codon (p.Glu238Gln) has been reported to be associated with VPS45-related disorder (PMID: 23738510). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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
A rare form of congenital neutropenia: VPS45 deficiency.	Karaatmaca B	Scandinavian journal of immunology	2020	PMID: 32037586
Severe congenital neutropenia with neurological impairment due to a homozygous VPS45 p.E238K mutation: A case report suggesting a genotype-phenotype correlation.	Meerschaut I	American journal of medical genetics. Part A	2015	PMID: 26358756
A congenital neutrophil defect syndrome associated with mutations in VPS45.	Vilboux T	The New England journal of medicine	2013	PMID: 23738510

Text-mined citations for rs782269909 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_007259.5(VPS45):c.712G>A (p.Glu238Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs782269909 ...