rs879255596

Variant names:

• chr18-58390680-G-A
• rs879255596
• NM_001144967.3:c.2690G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001144967.3(NEDD4L):​c.2690G>A​(p.Arg897Gln) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEDD4L NM_001144967.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 10.0
• Publications: 8 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 18-58390680-G-A is Pathogenic according to our data. Variant chr18-58390680-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225190.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144967.3. 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
	NEDD4L	NM_001144967.3	MANE Select	c.2690G>A	p.Arg897Gln	missense	Exon 29 of 31	NP_001138439.1
	NEDD4L	NM_001437337.1		c.3527G>A	p.Arg1176Gln	missense	Exon 25 of 27	NP_001424266.1
	NEDD4L	NM_001144968.2		c.2666G>A	p.Arg889Gln	missense	Exon 29 of 31	NP_001138440.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.2690G>A	p.Arg897Gln	missense	Exon 29 of 31	ENSP00000383199.2
	NEDD4L	ENST00000357895.9	TSL:1	c.2666G>A	p.Arg889Gln	missense	Exon 29 of 31	ENSP00000350569.4
	NEDD4L	ENST00000382850.8	TSL:1	c.2630G>A	p.Arg877Gln	missense	Exon 28 of 30	ENSP00000372301.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445542 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 717034

African (AFR) AF: 0.00 AC: 0 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 42972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25740

East Asian (EAS) AF: 0.00 AC: 0 AN: 39182

South Asian (SAS) AF: 0.00 AC: 0 AN: 83012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103388

Other (OTH) AF: 0.00 AC: 0 AN: 59788

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Jul 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as c.2690G>A (p.Arg897Gln). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 877 of the NEDD4L protein (p.Arg877Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with periventricular nodular heterotopia (PMID: 27694961). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 225190). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NEDD4L function (PMID: 27694961). For these reasons, this variant has been classified as Pathogenic.

Jun 05, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect associated with deregulation of mTORC and AKT activities and affecting neurogenesis, neuronal positioning, and terminal translocation (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 R897Q; This variant is associated with the following publications: (PMID: 28515470, 27694961, 36934385, 35599849, 34087865)

Periventricular nodular heterotopia 7 Pathogenic:2

Apr 26, 2018

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 16, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Periventricular nodular heterotopia with syndactyly, cleft palate and developmental delay Pathogenic:1

Apr 02, 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

Intellectual disability Uncertain:1

Apr 20, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.84		Loss of MoRF binding (P = 0.0323)
MVP		0.75
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.83
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs879255596; hg19: chr18-56057912;