Submissions for variant NM_001040142.2(SCN2A):c.2548C>T (p.Arg850Ter)

dbSNP: rs1553578503

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000585495	SCV000693005	likely pathogenic	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055515	SCV001219913	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-04-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg850*) 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 intellectual disability (PMID: 26350204). ClinVar contains an entry for this variant (Variation ID: 493288). 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.
GeneDx	RCV000585495	SCV002498883	pathogenic	not provided	2024-09-15	criteria provided, single submitter	clinical testing	Identified in one individual in a large cohort of patients with intellectual disability in the published literature (PMID: 26350204); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31440721, 33994118, 35982160, 35982159, 26350204)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252172	SCV002522943	pathogenic	See cases	2021-12-07	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV003126828	SCV003804016	pathogenic	Autism spectrum disorder	2020-09-30	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783819	SCV005397451	pathogenic	Episodic ataxia, type 9	2022-12-08	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>T) at coding position 2548 of the SCN2A gene that creates a premature termition sigl from an arginine codon at codon 850. As this change occurs in exon 15 of 27, this variant is predicted to generate a non-functiol allele through the expression of a truncated protein or the loss of SCN2A expression due to nonsense mediated decay. This is a previously reported variant (ClinVar) that has been observed in individuals with neurodevelopmental disorders including autism spectrum disorder and cognitive impairment (PMID: 35982159, 33004838). This variant is absent from the gnomAD population database (0 of approximately 250,000 alleles). Studies examining the functiol consequence of this variant have not been published, to our knowledge. However, loss of function is a known mechanism of disease for SCN2A (PMID: 28256214). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PS2, PVS1