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

gnomAD frequency: 0.00001  dbSNP: rs2064221873

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059822	SCV001224470	uncertain significance	Brugada syndrome 5	2024-01-11	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	2024-02-22	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.