Submissions for variant NM_001144967.3(NEDD4L):c.2677G>A (p.Glu893Lys)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433945	SCV000523429	pathogenic	not provided	2024-01-23	criteria provided, single submitter	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)
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000258896	SCV000923538	pathogenic	Periventricular nodular heterotopia 7	2024-09-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000258896	SCV001525360	pathogenic	Periventricular nodular heterotopia 7	2020-06-05	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000433945	SCV002171167	pathogenic	not provided	2021-08-29	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 873 of the NEDD4L protein (p.Glu873Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This missense change has been observed in individual(s) with NEDD4L-related conditions (PMID: 27694961, 28515470; Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NEDD4L function (PMID: 27694961). 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. ClinVar contains an entry for this variant (Variation ID: 225191). This variant is also known as c.2677G>A p.Glu893Lys.
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV000258896	SCV004227979	pathogenic	Periventricular nodular heterotopia 7		criteria provided, single submitter	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003493512	SCV004242408	likely pathogenic	Chromosome 5Q14.3 deletion syndrome, distal	2024-01-02	criteria provided, single submitter	clinical testing	Criteria applied: PS2,PS4_MOD,PM2_SUP,PP2,PP3
Chelly Lab, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg University - CNRS UMR 7104 - Inserm U 964	RCV000239759	SCV000267107	pathogenic	Periventricular nodular heterotopia with syndactyly, cleft palate and developmental delay	2016-04-03	no assertion criteria provided	research
OMIM	RCV000258896	SCV000328666	pathogenic	Periventricular nodular heterotopia 7	2023-08-23	no assertion criteria provided	literature only
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000258896	SCV000803719	pathogenic	Periventricular nodular heterotopia 7	2018-04-11	no assertion criteria provided	clinical testing