Submissions for variant NM_001040142.2(SCN2A):c.4303C>T (p.Arg1435Ter)

dbSNP: rs796053138

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485232	SCV000567713	pathogenic	not provided	2023-07-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28379373, 30564305, 31780880, 32090326, 28191889, 33004838, 30813884, 26993267, Gowda2021[Case Report], 31440721, 35431799)
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000585884	SCV000693773	likely pathogenic	Developmental and epileptic encephalopathy, 11	2018-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640630	SCV000762224	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1435*) in the SCN2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN2A are known to be pathogenic (PMID: 28379373). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autism spectrum disorders, severe intellectual disability, and/or seizures (PMID: 26993267, 28379373). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 419721). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000585884	SCV000803822	likely pathogenic	Developmental and epileptic encephalopathy, 11	2017-09-13	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001257715	SCV001434526	likely pathogenic	Intellectual disability	2020-04-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000485232	SCV001448115	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000485232	SCV002020013	pathogenic	not provided	2021-10-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004023125	SCV004944217	pathogenic	Inborn genetic diseases	2024-02-16	criteria provided, single submitter	clinical testing	The c.4303C>T (p.R1435*) alteration, located in exon 23 (coding exon 22) of the SCN2A gene, consists of a C to T substitution at nucleotide position 4303. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1435. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. _x000D_ _x000D_ for autosomal dominant SCN2A-related neurodevelopmental disorder; however, its clinical significance for autosomal dominant SCN2A-related developmental and epileptic encephalopathy and autosomal dominant SCN2A-related benign familial infantile seizures is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with features consistent with SCN2A-related neurodevelopmental disorder, including multiple cases of reported de novo occurrence (Trump, 2016; Wolff, 2017; Fernández-Marmiesse, 2019; Zeng, 2022; Gowda, 2023). Based on the available evidence, this alteration is classified as pathogenic.
3billion	RCV000585884	SCV005906148	pathogenic	Developmental and epileptic encephalopathy, 11	2023-08-29	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000419721 /PMID: 26993267). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Neurology Department, Shenzhen Children's Hospital	RCV001848850	SCV002099471	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-02-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735558	SCV005365810	pathogenic	SCN2A-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The SCN2A c.4303C>T variant is predicted to result in premature protein termination (p.Arg1435*). This is a recurrent de novo variant that has been reported in multiple patients with SCN2A related autosomal dominant disorders (Trump et al. 2016. PubMed ID: 26993267; Wolff et al. 2017. PubMed ID: 28379373; Additional File 5 Data 2, Guo et al. 2018. PubMed ID: 30564305; Fernández-Marmiesse et al. 2019. PubMed ID: 31780880). This variant has not been reported in a large population database, indicating it is rare. Nonsense variants in SCN2A are expected to be pathogenic. This variant is interpreted as pathogenic.