Submissions for variant NM_001040142.2(SCN2A):c.2674G>A (p.Val892Ile)

dbSNP: rs121917751

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189121	SCV000242753	likely pathogenic	not provided	2021-01-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This substitution is predicted to be within the transmembrane segment S5 of the second homologous domain; This variant is associated with the following publications: (PMID: 15048894, 28717674, 29215089, 29655203, 29429461, 32090326)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527590	SCV000639618	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 892 of the SCN2A protein (p.Val892Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with benign familial neonatal-infantile seizures (PMID: 15048894, 29215089). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12878). 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 SCN2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000527590	SCV000898955	likely pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2018-08-15	criteria provided, single submitter	clinical testing	SCN2A NM_021007.2 exon 16 p.Val892Ile (c.2674G>A): This variant has been reported in the literature in at least 2 individuals with Benign Familial Neonatal-Infantile Epilepsy (BFNIE), segregating with disease in at least 5 affected family members (Berkovic 2004 PMID:15048894, Zeng 2018 PMID:29215089). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:12878). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000189121	SCV002496530	likely pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224096	SCV003920430	likely pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11; Episodic ataxia, type 9	2021-11-11	criteria provided, single submitter	clinical testing	SCN2A NM_021007.2 exon 16 p.Val892Ile (c.2674G>A): This variant has been reported in the literature in at least 2 individuals with Benign Familial Neonatal-Infantile Epilepsy (BFNIE), segregating with disease in at least 5 affected family members (Berkovic 2004 PMID:15048894, Zeng 2018 PMID:29215089). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:12878). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000189121	SCV005198141	likely pathogenic	not provided	2023-01-12	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV003224096	SCV005416828	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11; Episodic ataxia, type 9		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Moderate+PP1_Strong+PS2_Moderate+PP4
Neuberg Centre For Genomic Medicine, NCGM	RCV005208119	SCV005849531	likely pathogenic	Developmental and epileptic encephalopathy, 11	2023-06-22	criteria provided, single submitter	clinical testing	The observed missense c.2674G>A(p.Val892Ile) variant in SCN2A gene has been previously observed in multiple individuals affected with Benign Familial Neonatal-Infantile Seizures (Zeng Q, et al, 2018; Berkovic SF, et al., 2004). This variant has also been observed to segregate with disease in related individuals. This variant is absent in the gnomAD Exomes. The variant has been submitted to ClinVar as Pathogenic / Likely Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Tolerated and MutationTaster - Disease causing) predict conflicting evidence on protein structure and function for this variant. The reference amino acid at this position in SCN2A gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 892 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic.
OMIM	RCV000013738	SCV000033985	pathogenic	Seizures, benign familial infantile, 3	2004-04-01	no assertion criteria provided	literature only
Neurology Department, Shenzhen Children's Hospital	RCV000013738	SCV002099465	pathogenic	Seizures, benign familial infantile, 3	2022-02-16	no assertion criteria provided	clinical testing