Submissions for variant NM_001037.5(SCN1B):c.178C>T (p.Arg60Cys)

gnomAD frequency: 0.00001  dbSNP: rs2064221873

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059822	SCV001224470	uncertain significance	Brugada syndrome 5	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 60 of the SCN1B protein (p.Arg60Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive developmental and epileptic encephalopathy (PMID: 33901312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 854719). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN1B function (PMID: 33901312). 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.
GeneDx	RCV001759815	SCV001987751	likely pathogenic	not provided	2025-03-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on the conductance-voltage relationship, recovery from fast inactivation, and rate of channel fast inactivation compared to wild type (PMID: 33901312); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24848745, 36291443, 33901312)
Ambry Genetics	RCV002402430	SCV002714432	uncertain significance	Cardiovascular phenotype	2021-07-27	criteria provided, single submitter	clinical testing	The p.R60C variant (also known as c.178C>T), located in coding exon 2 of the SCN1B gene, results from a C to T substitution at nucleotide position 178. The arginine at codon 60 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in the homozygous state in two siblings with early infantile epileptic encephalopathy whose heterozygous parents were unaffected. Functional studies suggested this variant may impact sodium channel function (Scala M et al. Epilepsia. 2021 Jun;62(6):e82-e87). This variant was also reported in a control subject participating in an epilepsy study; however, detailed clinical information was not available (Della Mina E et al. Eur. J. Hum. Genet., 2015 Mar;23:354-62). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789391	SCV005400256	likely pathogenic	Developmental and epileptic encephalopathy, 52	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with generalised epilepsy with febrile seizures plus, type 1 (GEFS+: MIM#604233) and developmental and epileptic encephalopathy 52 (MIM#617350). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene has been reported to be associated with both autosomal recessive and autosomal dominant epilepsy (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. The disease penetrance of variants associated with GEFS+ is found to be 62-76% (PMID: 36291443). (I) 0115 - Variants in this gene are known to have variable expressivity. Families with SCN1B-related epilepsy may have members with that same variant that are seizure-free, have febrile seizures or have epilepsy (most frequently FS+) (PMID: 36291443). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3: 2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Immunoglobulin V-set domain (DECIPHER). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. The p.(Arg60His) and p.(Arg60Leu) variants have been classified as VUS by clinical laboratories in ClinVar. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported in homozygous sisters with developmental delay and epilepsy (PMID:33901312). This variant has also been classified as a VUS by clinical laboratories in ClinVar without known association with epilepsy. (SP) 1010 - Functional evidence for this variant is inconclusive. Voltage-clamp studies showed some effect on neuronal sodium channel potential and channel availability (PMID:33901312). (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant: c.363C>G; p.(Cys121Trp) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign