VCV000016748.12 - ClinVar

NM_001972.4(ELANE):c.640G>A (p.Gly214Arg)

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.

(7)

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_001972.4(ELANE):c.640G>A (p.Gly214Arg)

Variation ID: 16748 Accession: VCV000016748.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.3 19: 856000 (GRCh38) [ NCBI UCSC ] 19: 856000 (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	May 29, 2016	Mar 30, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001972.4:c.640G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001963.1:p.Gly214Arg	missense
NC_000019.10:g.856000G>A
NC_000019.9:g.856000G>A
NG_007274.1:g.1336G>A
NG_009627.1:g.8710G>A
LRG_46:g.1336G>A
LRG_57:g.8710G>A
LRG_57t1:c.640G>A
	P08246:p.Gly214Arg

... more HGVS ... less HGVS

Protein change

G214R

Other names

G185R

Canonical SPDI

NC_000019.10:855999: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.

Links

ClinGen: CA281059 UniProtKB: P08246#VAR_038625 OMIM: 130130.0011 dbSNP: rs137854451 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.
ELANE		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	557	600

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.
Neutropenia, severe congenital, 1, autosomal dominant	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV000018232.34
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 30, 2015	RCV000214338.2
Cyclical neutropenia	Pathogenic (1)	criteria provided, single submitter	Apr 27, 2018	RCV001336413.1
Cyclical neutropenia Neutropenia, severe congenital, 1, autosomal dominant	Pathogenic (1)	criteria provided, single submitter	Sep 28, 2022	RCV001851904.6

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 30, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000278970.9 First in ClinVar: May 29, 2016 Last updated: May 29, 2016	Comment: The G214R missense mutation in the ELANE gene has been reported previously (as G185R) in association with congenital neutropenia (Dale et al., 2000; BellannÃ©-Chantelot et … (more) The G214R missense mutation in the ELANE gene has been reported previously (as G185R) in association with congenital neutropenia (Dale et al., 2000; BellannÃ©-Chantelot et al., 2004). The G214R mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. (less)
Pathogenic (Dec 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neutropenia, severe congenital, 1, autosomal dominant Affected status: yes Allele origin: de novo	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital Accession: SCV001499920.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Publications: PubMed (6) PubMed: 11001877‚ 15657182‚ 16079102‚ 28073911‚ 30386760‚ 3229910 Number of individuals with the variant: 1 Age: 0-9 years Sex: female Ethnicity/Population group: East Asia Geographic origin: China
Pathogenic (Apr 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cyclical neutropenia Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001529791.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (3) PubMed: 11001877‚ 15657182‚ 28073911 Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant was previously reported as disease-causing [PMID: 11001877, 15657182, 28073911, described … (more) This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant was previously reported as disease-causing [PMID: 11001877, 15657182, 28073911, described as p.G185R] (less)
Pathogenic (May 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Neutropenia, severe congenital, 1, autosomal dominant Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV003924305.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023
Pathogenic (Sep 28, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neutropenia, severe congenital, 1, autosomal dominant Cyclical neutropenia 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: SCV002238566.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 23463630‚ 25427142‚ 15657182‚ 28073911‚ 11001877‚ 16079102‚ 30386760 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly214 amino acid residue in ELANE. Other variant(s) that disrupt this … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly214 amino acid residue in ELANE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23463630, 25427142). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ELANE function (PMID: 15657182, 28073911). 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 ELANE protein function. ClinVar contains an entry for this variant (Variation ID: 16748). This variant is also known as G185R. This missense change has been observed in individual(s) with clinical features of severe congenital neutropenia (PMID: 11001877, 16079102, 30386760). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 214 of the ELANE protein (p.Gly214Arg). (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neutropenia, severe congenital, 1, autosomal dominant (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV004801916.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Clinical Features: Neutropenia (present) , Chronic neutropenia (present)
Pathogenic (Jan 01, 2008)	no assertion criteria provided Method: literature only	NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038511.3 First in ClinVar: Apr 04, 2013 Last updated: Jul 21, 2018	Publications: PubMed (3) PubMed: 11001877‚ 14962902‚ 18028488 Comment on evidence: In patients with severe congenital neutropenia (SCN1; 202700), Dale et al. (2000) and Bellanne-Chantelot et al. (2004) identified a heterozygous 4924G-A transition in exon 5 … (more) In patients with severe congenital neutropenia (SCN1; 202700), Dale et al. (2000) and Bellanne-Chantelot et al. (2004) identified a heterozygous 4924G-A transition in exon 5 of the ELA2 gene, resulting in a gly185-to-arg (G185R) substitution. Rosenberg et al. (2007) identified the G185R mutation in 4 of 82 unrelated patients with SCN1. Patients with the G185R mutation had a particularly severe disease course, and 2 developed MDS/AML at 10 and 15 years, respectively. (less)

Comment:

The G214R missense mutation in the ELANE gene has been reported previously (as G185R) in association with congenital neutropenia (Dale et al., 2000; BellannÃ©-Chantelot et al., 2004). The G214R mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly214 amino acid residue in ELANE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23463630, 25427142). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ELANE function (PMID: 15657182, 28073911). 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 ELANE protein function. ClinVar contains an entry for this variant (Variation ID: 16748). This variant is also known as G185R. This missense change has been observed in individual(s) with clinical features of severe congenital neutropenia (PMID: 11001877, 16079102, 30386760). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 214 of the ELANE protein (p.Gly214Arg).

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
Clinical, Laboratory, and Molecular Characteristics and Remission Status in Children With Severe Congenital and Non-congenital Neutropenia.	Gong RL	Frontiers in pediatrics	2018	PMID: 30386760
A Truncated Granulocyte Colony-stimulating Factor Receptor (G-CSFR) Inhibits Apoptosis Induced by Neutrophil Elastase G185R Mutant: IMPLICATION FOR UNDERSTANDING CSF3R GENE MUTATIONS IN SEVERE CONGENITAL NEUTROPENIA.	Qiu Y	The Journal of biological chemistry	2017	PMID: 28073911
The diversity of mutations and clinical outcomes for ELANE-associated neutropenia.	Makaryan V	Current opinion in hematology	2015	PMID: 25427142
The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.	Germeshausen M	Human mutation	2013	PMID: 23463630
Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia.	Rosenberg PS	British journal of haematology	2008	PMID: 18028488
A comparison of the defective granulopoiesis in childhood cyclic neutropenia and in severe congenital neutropenia.	Sera Y	Haematologica	2005	PMID: 16079102
Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes.	Massullo P	Blood	2005	PMID: 15657182
Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register.	Bellanné-Chantelot C	Blood	2004	PMID: 14962902
Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.	Dale DC	Blood	2000	PMID: 11001877
HIV risk (still) low for health care workers.	-	International nursing review	1988	PMID: 3229910

Text-mined citations for rs137854451 ...

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_001972.4(ELANE):c.640G>A (p.Gly214Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137854451 ...