Submissions for variant NM_001037.5(SCN1B):c.472G>C (p.Val158Leu)

gnomAD frequency: 0.00002  dbSNP: rs138450474

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857033	SCV002275994	uncertain significance	Brugada syndrome 5	2023-06-29	criteria provided, single submitter	clinical testing	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 433138). This missense change has been observed in individual(s) with clinical features of SCN1B-related conditions (PMID: 29358611). This variant is present in population databases (rs138450474, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 158 of the SCN1B protein (p.Val158Leu). The SCN1B gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001037.5, and corresponds to NM_199037.3:c.*5042G>C in the primary transcript.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252143	SCV002523300	uncertain significance	See cases	2019-10-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PM3
Ambry Genetics	RCV002341177	SCV002638318	uncertain significance	Cardiovascular phenotype	2023-05-18	criteria provided, single submitter	clinical testing	The p.V158L variant (also known as c.472G>C), located in coding exon 4 of the SCN1B gene, results from a G to C substitution at nucleotide position 472. The valine at codon 158 is replaced by leucine, an amino acid with highly similar properties. This alteration has been detected in an individual with rolandic or atypical rolandic epilepsy (Bobbili DR et al. Eur. J. Hum. Genet., 2018 02;26:258-264). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of Brugada syndrome; however, its contribution to the development of SCN1B-related developmental and epileptic encephalopathy and SCN1B-related epilepsy is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV003456401	SCV004183632	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	SCN1B: PM5, PP3
GeneDx	RCV003456401	SCV005080248	uncertain significance	not provided	2024-05-07	criteria provided, single submitter	clinical testing	Reported previously in a patient with rolandic epilepsy (RE); however, no further clinical or segregation information was provided (PMID: 29358611); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 29758173, 29358611)
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656062	SCV000588338	pathogenic	Self-limited epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15