Submissions for variant NM_001040142.2(SCN2A):c.5705G>A (p.Arg1902His)

gnomAD frequency: 0.00004  dbSNP: rs747710683

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498889	SCV000589465	uncertain significance	not provided	2017-10-09	criteria provided, single submitter	clinical testing	The R1902H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different missense variant at the same position (R1902C) has been reported previously in an individual with autism; however, it was not detected in this individual's affected sibling (Weiss et al., 2003). The R1902H variant is observed in 5/24026 (0.02%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). This substitution occurs at a conserved position predicted to be within the C-terminal cytoplasmic region of the SCN2A protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R1902H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is apathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857004	SCV002197559	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-08-13	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 1902 of the SCN2A protein (p.Arg1902His). This variant is present in population databases (rs747710683, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 431900). 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%. 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.
Ambry Genetics	RCV003243150	SCV003952908	likely benign	Inborn genetic diseases	2023-05-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.