Submissions for variant NM_001037.5(SCN1B):c.461T>C (p.Met154Thr)

dbSNP: rs1432198305

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000646748	SCV000768533	uncertain significance	Brugada syndrome 5	2019-03-26	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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SCN1B-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 154 of the SCN1B protein (p.Met154Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. The SCN1B gene has multiple clinically relevant transcripts. The p.Met154Thr variant occurs in alternate transcript NM_001037.4, which corresponds to c.*5031T>C in NM_199037.3, the primary transcript listed in the Methods.
GeneDx	RCV001584490	SCV001820757	uncertain significance	not provided	2019-12-10	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002331208	SCV002633399	uncertain significance	Cardiovascular phenotype	2022-06-27	criteria provided, single submitter	clinical testing	The c.461T>C (p.M154T) alteration is located in exon 4 (coding exon 4) of the SCN1B gene. This alteration results from a T to C substitution at nucleotide position 461, causing the methionine (M) at amino acid position 154 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004735710	SCV005366109	uncertain significance	SCN1B-related disorder	2024-06-13	no assertion criteria provided	clinical testing	The SCN1B c.461T>C variant is predicted to result in the amino acid substitution p.Met154Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.