rs137854451

Variant names:

• chr19-856000-G-A
• rs137854451
• NM_001972.4:c.640G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-856000-G-A
• chr19-856000-G-C
• chr19-856000-G-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001972.4(ELANE):​c.640G>A​(p.Gly214Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G214E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.40
• Publications: 25 publications found

Genes affected

ELANE (HGNC:3309): (elastase, neutrophil expressed) Elastases form a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. Humans have six elastase genes which encode structurally similar proteins. The encoded preproprotein is proteolytically processed to generate the active protease. Following activation, this protease hydrolyzes proteins within specialized neutrophil lysosomes, called azurophil granules, as well as proteins of the extracellular matrix. The enzyme may play a role in degenerative and inflammatory diseases through proteolysis of collagen-IV and elastin. This protein also degrades the outer membrane protein A (OmpA) of E. coli as well as the virulence factors of such bacteria as Shigella, Salmonella and Yersinia. Mutations in this gene are associated with cyclic neutropenia and severe congenital neutropenia (SCN). This gene is present in a gene cluster on chromosome 19. [provided by RefSeq, Jan 2016]

ELANE Gene-Disease associations (from GenCC):

• neutropenia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• cyclic hematopoiesis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_001972.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-856001-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1301410.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 53 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.71822 (below the threshold of 3.09). Trascript score misZ: -0.55649 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant severe congenital neutropenia, cyclic hematopoiesis, neutropenia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 19-856000-G-A is Pathogenic according to our data. Variant chr19-856000-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELANE	NM_001972.4	c.640G>A	p.Gly214Arg	missense_variant	Exon 5 of 5	ENST00000263621.2	NP_001963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELANE	ENST00000263621.2	c.640G>A	p.Gly214Arg	missense_variant	Exon 5 of 5	1	NM_001972.4	ENSP00000263621.1
ELANE	ENST00000590230.5	c.640G>A	p.Gly214Arg	missense_variant	Exon 6 of 6	5		ENSP00000466090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:4

Dec 20, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 08, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 25, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cyclical neutropenia;C1859966:Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:1

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of severe congenital neutropenia (PMID: 11001877, 16079102, 30386760). This variant is also known as G185R. ClinVar contains an entry for this variant (Variation ID: 16748). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ELANE function (PMID: 15657182, 28073911). 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. For these reasons, this variant has been classified as Pathogenic. -

Cyclical neutropenia Pathogenic:1

Apr 27, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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] -

not provided Pathogenic:1

Jun 30, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G214R missense mutation in the ELANE gene has been reported previously (as G185R) in association with congenital neutropenia (Dale et al., 2000; Bellanné-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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	.;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;H
PhyloP100		4.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.2	.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.97		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.99
MPC		1.5
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.96
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137854451; hg19: chr19-856000; COSMIC: COSV55049733; COSMIC: COSV55049733;