NM_001972.4:c.377C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001972.4(ELANE):c.377C>T(p.Ser126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S126W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ELANE
NM_001972.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: -0.811

Publications

20 publications found

Variant links:

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

ELANE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 1 benign, 21 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 chr19-855574-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1452300.

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, 0.983

PP5

Variant 19-855574-C-T is Pathogenic according to our data. Variant chr19-855574-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	NM_001972.4	MANE Select	c.377C>T	p.Ser126Leu	missense	Exon 4 of 5	NP_001963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	ENST00000263621.2	TSL:1 MANE Select	c.377C>T	p.Ser126Leu	missense	Exon 4 of 5	ENSP00000263621.1
	ELANE	ENST00000590230.5	TSL:5	c.377C>T	p.Ser126Leu	missense	Exon 5 of 6	ENSP00000466090.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720480

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111722

Other (OTH)

AF:

0.00

AC:

AN:

60276

GnomAD4 genome

Cov.:

Alfa

AF:

0.000180

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neutropenia, severe congenital, 1, autosomal dominant

Pathogenic:4

Jan 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jun 12, 2024

Department of Genetics, Sultan Qaboos University Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

Dec 01, 2024

Laboratory of Immunopathology and Genetics, Medical Laboratory of Pediatric Oncology and Hematology, Central Clinical Hospital of the Medical University of Lodz

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 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

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Pathogenic:1

Dec 21, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Pathogenic:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 126 of the ELANE protein (p.Ser126Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cyclic neutropenia and severe congenital neutropenia (PMID: 11001877, 14962902, 16079102, 16737875, 18611981, 20582973, 22758217, 23463630). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ser97Leu. ClinVar contains an entry for this variant (Variation ID: 16745). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ELANE function (PMID: 16551967, 26567890). For these reasons, this variant has been classified as Pathogenic.

Decreased total neutrophil count

Pathogenic:1

Nov 14, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as pathogenic by multiple clinical laboratories (ClinVar). This variant has also been reported in multiple unrelated individuals with cyclic neutropenia (CyN) or severe congenital neutropenia (SCN) (PMID: 38840904) Evidence in support of benign classification: Same amino acid change has been observed in placental mammals. Additional information: Variant is predicted to result in a missense amino acid change from serine to leucine; This variant is heterozygous; This gene is associated with autosomal dominant disease; The mechanism of disease for this gene is not clearly established. However, haploinsufficiency is unlikely a mechanism of disease (PMID: 33968054, 31248972); Variants in this gene are known to have variable expressivity. The same variant can lead to either cyclic or severe congenital neutropenia (PMID: 20301705); Inheritance information for this variant is not currently available in this individual.

ELANE-related disorder

Pathogenic:1

Aug 01, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ELANE c.377C>T variant is predicted to result in the amino acid substitution p.Ser126Leu. This variant is also described using legacy nomenclature as p.Ser97Leu, has been reported in multiple individuals with congenital neutropenia (Dale et al. 2000. PubMed ID: 11001877; Sera et al. 2005. PubMed ID: 16079102; Newburger et al. 2010. PubMed ID: 20582973; Wali et al. 2012. PubMed ID: 22758217; Gong et al. 2018. PubMed ID: 30386760). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.4

PhyloP100

-0.81

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.59

Sift

Benign

0.25

Sift4G

Benign

0.29

Polyphen

0.43

Vest4

0.25

MutPred

0.89

Loss of glycosylation at S126 (P = 0.0876)

MVP

0.98

MPC

0.47

ClinPred

0.32

GERP RS

2.1

Varity_R

0.24

gMVP

0.87

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over