Submissions for variant NM_001165963.4(SCN1A):c.664C>T (p.Arg222Ter)

dbSNP: rs121918624

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000188841	SCV000111477	pathogenic	not provided	2016-05-03	criteria provided, single submitter	clinical testing
Center for Bioinformatics, Peking University	RCV000032604	SCV000221894	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
GeneDx	RCV000188841	SCV000242471	pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing	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; Published functional studies demonstrate an inability to generate sodium current and slower kinetics of recovery from inactivation (Bechi et al., 2012); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26096185, 14738421, 30321769, 22409937, 23195492, 25525159, 28837158, 22150645, 11359211, 19522081, 24168886, 29100083, 31780880, 31864146, 32090326, 29573403, 33278787)
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000032604	SCV000693790	likely pathogenic	Severe myoclonic epilepsy in infancy	2018-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000032604	SCV000697774	pathogenic	Severe myoclonic epilepsy in infancy	2016-05-04	criteria provided, single submitter	clinical testing	Variant summary: The SCN1A c.664C>T (p.Arg222X) variant results in a premature termination codon, predicted to cause a truncated or absent SCN1A protein, which is a commonly known mechanism for disease. The variant is absent in 116,872 control chromosomes and has been reported by multiple reputable clinical labs as pathogenic. The literature reports this variant in numerous SMEI patients, many of whom have confirmed de novo inheritance. Functional study proved that variant did not generate Na+current and showed significantly slower kinetics of recovery from inactivation compared to WT (Bechi_2012). Taken together, this variant has been classified as pathogenic.
Ambry Genetics	RCV002316194	SCV000851275	pathogenic	Inborn genetic diseases	2016-10-03	criteria provided, single submitter	clinical testing	The p.R222* pathogenic mutation (also known as c.664C>T), located in coding exon 5 of the SCN1A gene, results from a C to T substitution at nucleotide position 664. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been reported in an individual with severe myoclonic epilepsy of infancy (Claes L et al. Am. J. Hum. Genet., 2001 Jun;68:1327-32). In addition to the clinical data presented in the literature, 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.
Fulgent Genetics, Fulgent Genetics	RCV000763461	SCV000894238	pathogenic	Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001037392	SCV001200803	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg222*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SCN1A-related conditions (PMID: 11359211, 23195492, 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12889). For these reasons, this variant has been classified as Pathogenic.
Diagnostic Laboratory, Strasbourg University Hospital	RCV001257707	SCV001434518	pathogenic	Intellectual disability	2020-04-20	criteria provided, single submitter	clinical testing
3billion	RCV000032604	SCV002058989	pathogenic	Severe myoclonic epilepsy in infancy	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012889, PMID:11359211). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26096185, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003388823	SCV004100725	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2023-10-30	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS2,PS4,PS3_SUP,PM2_SUP
OMIM	RCV000032604	SCV000056358	pathogenic	Severe myoclonic epilepsy in infancy	2001-06-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000032604	SCV000805025	pathogenic	Severe myoclonic epilepsy in infancy	2016-12-21	no assertion criteria provided	clinical testing