Submissions for variant NM_001165963.4(SCN1A):c.302G>A (p.Arg101Gln)

dbSNP: rs121917918

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000188829	SCV000111453	pathogenic	not provided	2015-09-11	criteria provided, single submitter	clinical testing
Center for Bioinformatics, Peking University	RCV000059400	SCV000221968	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
GeneDx	RCV000188829	SCV000242458	pathogenic	not provided	2021-03-17	criteria provided, single submitter	clinical testing	Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This substitution is predicted to be within the N-terminal cytoplasmic domain.; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27465585, 25885068, 24328833, 23195492, 23808377, 23158734, 14738421, 15508916, 15277629, 17347258, 17561957, 18930999, 29056246, 30945278, 32090326)
Invitae	RCV000550639	SCV000633844	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-05-05	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Dravet syndrome (PMID: 14738421, 23195492, 23808377, 24328833, 25986186). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg101 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20431604, 23195492). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. ClinVar contains an entry for this variant (Variation ID: 68528). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 101 of the SCN1A protein (p.Arg101Gln).
CeGaT Center for Human Genetics Tuebingen	RCV000188829	SCV001249711	pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197275	SCV001367912	pathogenic	Migraine, familial hemiplegic, 3	2019-05-07	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PM1,PP2.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000059400	SCV002768227	pathogenic	Severe myoclonic epilepsy in infancy	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN1A-related epilepsy (PMID: 28488083). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative changes to tryptophan and leucine have been previously reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo or to have been inherited from a mosaic parent, in multiple individuals with Dravet syndrome (PMID: 23808377, 23195492, 24328833, 22071555, 25986186). This variant is reported as pathogenic in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Lifecell International Pvt. Ltd	RCV000059400	SCV003804188	pathogenic	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	The missense variant NM_001165963.4 (SCN1A):c.302G>A (p.Arg101Gln) causes the same amino acid change as a previously established pathogenic variant. The p.Arg101Gln variant is novel (not in any individuals) in gnomAD. The p.Arg101Gln variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene SCN1A has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 5.22. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). This variant has previously been reported for Dravet syndrome by Sun H et al., 2010. The gene SCN1A contains 539 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 5 variants within 6 amino acid positions of the variant p.Arg101Gln have been shown to be pathogenic, while none have been shown to be benign. The p.Arg101Gln missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 101 of SCN1A is conserved in all mammalian species. The nucleotide c.302 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot	RCV000059400	SCV000090924	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided