rs879255597

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001144967.3(NEDD4L):c.2677G>A(p.Glu893Lys) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEDD4L
NM_001144967.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.96

Publications

13 publications found

Variant links:

Genes affected

NEDD4L (HGNC:7728): (NEDD4 like E3 ubiquitin protein ligase) This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

NEDD4L Gene-Disease associations (from GenCC):

periventricular nodular heterotopia 7
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
periventricular nodular heterotopia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NEDD4L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

PP5

Variant 18-58390667-G-A is Pathogenic according to our data. Variant chr18-58390667-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 225191.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
NEDD4L	NM_001144967.3 link	c.2677G>A	p.Glu893Lys	missense_variant	Exon 29 of 31	ENST00000400345.8	NP_001138439.1	Q96PU5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8 link	c.2677G>A	p.Glu893Lys	missense_variant	Exon 29 of 31	1	NM_001144967.3	ENSP00000383199.2		Q96PU5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1439208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713364

African (AFR)

AF:

0.00

AC:

AN:

33210

American (AMR)

AF:

0.00

AC:

AN:

42040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25668

East Asian (EAS)

AF:

0.00

AC:

AN:

38926

South Asian (SAS)

AF:

0.00

AC:

AN:

82332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099776

Other (OTH)

AF:

0.00

AC:

AN:

59558

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Periventricular nodular heterotopia 7

Pathogenic:5

Sep 01, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2018

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 28, 2025

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The first report of this variant was in PMID: 27694961 and PMID: 28515470. Our patient was described in PMID: 34087865. This 2-year-old boy was polystigmatized and showed significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The proband showed also other symptoms, outside PVNH7 symptomatology, that were also present in the proband’s older brother (such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus). Brother did not carry the variant; thus, these symptoms are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family. -

Jun 05, 2020

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]. -

not provided

Pathogenic:2

Jan 23, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: decrease in protein stability and increased Akt phosphorylation (PMID: 27694961); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.2677G>A p.(Glu893Lys); This variant is associated with the following publications: (PMID: 31028281, 28515470, 27694961, 34087865, 35599849, 36934385) -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 873 of the NEDD4L protein (p.Glu873Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NEDD4L-related conditions (PMID: 27694961, 28515470; internal data). In at least one individual the variant was observed to be de novo. This variant is also known as c.2677G>A p.Glu893Lys. ClinVar contains an entry for this variant (Variation ID: 225191). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NEDD4L protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NEDD4L function (PMID: 27694961). For these reasons, this variant has been classified as Pathogenic. -

Periventricular nodular heterotopia with syndactyly, cleft palate and developmental delay

Pathogenic:1

Apr 03, 2016

Chelly Lab, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg University - CNRS UMR 7104 - Inserm U 964

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Chromosome 5Q14.3 deletion syndrome, distal

Pathogenic:1

Jan 02, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS2,PS4_MOD,PM2_SUP,PP2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

.;T;.;.;.;.;.;.;.;.;.;.;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;.;D;D;D;.;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.0

.;M;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.7

D;D;.;D;D;D;D;D;.;D;D;.;.

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

D;D;.;D;D;D;D;D;.;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;.;D

Polyphen

0.97

D;D;.;D;.;.;.;D;D;.;.;.;.

Vest4

0.77

MutPred

0.76

.;Gain of MoRF binding (P = 0.003);.;.;.;.;.;.;.;.;.;.;.;

MVP

0.83

MPC

2.0

ClinPred

1.0

GERP RS

5.7

Varity_R

0.83

gMVP

0.89

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over