Submissions for variant NM_001040142.2(SCN2A):c.5753G>A (p.Arg1918His)

gnomAD frequency: 0.00015  dbSNP: rs201718767

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002318864	SCV000851810	uncertain significance	Inborn genetic diseases	2016-12-08	criteria provided, single submitter	clinical testing	The p.R1918H variant (also known as c.5753G>A), located in coding exon 26 of the SCN2A gene, results from a G to A substitution at nucleotide position 5753. The arginine at codon 1918 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in one individual with febrile and tonic-clonic seizures; however, it was absent in the individual's niece who had pyknoleptic daily clusters of absence seizures. Of note, the alteration was not detected in three additional unaffected family members or in 92 controls (Haug K et al. Epilepsy Res., 2001 Dec;47:243-6). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822218	SCV000963009	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1918 of the SCN2A protein (p.Arg1918His). This variant is present in population databases (rs201718767, gnomAD 0.02%). This missense change has been observed in individual(s) with childhood absence epilepsy and developmental and epileptic encephalopathy and/or epilepsy of infancy with migrating focal seizures (PMID: 11738931, 33000761, 35715422). ClinVar contains an entry for this variant (Variation ID: 590198). 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 not expected to disrupt SCN2A protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 28087622). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000997270	SCV001152498	uncertain significance	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001329202	SCV001520576	uncertain significance	Developmental and epileptic encephalopathy, 11	2020-08-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000997270	SCV001815252	likely benign	not provided	2019-02-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30564305, 27262167, 22029951, 11738931)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224383	SCV003920429	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11; Episodic ataxia, type 9	2021-03-30	criteria provided, single submitter	clinical testing	SCN2A NM_001040142.1 exon 27 p.Arg1918His (c.5753G>A): This variant has been reported in the literature in 1 individual with idiopathic generalized epilepsy, but did not segregate with disease in 1 affected family member (Haug 2001 PMID:11738931). This variant is present in 19/125972 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201718767). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Athena Diagnostics	RCV000997270	SCV004230008	uncertain significance	not provided	2024-02-12	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 28087622)