Submissions for variant NM_001040142.2(SCN2A):c.1831_1832del (p.Leu611fs)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostic Laboratory, Strasbourg University Hospital	RCV001257732	SCV001434544	pathogenic	Intellectual disability	2020-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001879979	SCV002222290	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-06-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu611Valfs*35) 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: 23020937, 25849321). This variant is also known as c.1827_1828del (p.D609fs). ClinVar contains an entry for this variant (Variation ID: 978936). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SCN2A function (PMID: 30813884). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002411919	SCV002716298	pathogenic	Inborn genetic diseases	2019-08-22	criteria provided, single submitter	clinical testing	The c.1831_1832delCT pathogenic mutation, located in coding exon 11 of the SCN2A gene, results from a deletion of two nucleotides at nucleotide positions 1831 to 1832, causing a translational frameshift with a predicted alternate stop codon (p.L611Vfs*35). This mutation was detected as de novo in an individual with intellectual disability, aggressive behavior, and dysmorphic facial features (Rauch A et al. Lancet, 2012 Nov;380:1674-82). In one paper, authors showed that this mutation results in a complete loss of voltage-gated sodium channel mediated currents in whole cell patch clamp studies (Begemann A et al. Mol. Med., 2019 02;25:6). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV003481039	SCV004225947	pathogenic	not provided	2022-06-07	criteria provided, single submitter	clinical testing	PM2, PS2, PVS1
Breakthrough Genomics, Breakthrough Genomics	RCV004596433	SCV005088770	pathogenic	Developmental and epileptic encephalopathy, 11	2022-04-11	criteria provided, single submitter	clinical testing	This variant was previously reported in a patient with intellectual disability in de novo heterozygous state [PMID: 30813884]. Loss-of-function variants in SCN2A generally result in autism, developmental delay, and sometimes seizures that begin later in life [PMID: 22495306, 23020937, 24650168, 34156984].

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