Submissions for variant NM_001037.5(SCN1B):c.367G>A (p.Val123Ile)

gnomAD frequency: 0.00002  dbSNP: rs754215948

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000171042	SCV000223606	uncertain significance	not provided	2015-09-16	criteria provided, single submitter	clinical testing	p.Val123Ile (GTC>ATC): c.367 G>A in exon 3 of the SCN1B gene (NM_001037.4). The V123I missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. V123I alters a conserved position in the SCN1B protein and another missense mutation in this region of the protein has been reported in association with generalized epilepsy with febrile seizures plus (GEFS+) (Wallace et al., 1998). However, the V123I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether V123I is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI,EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001315548	SCV001506126	uncertain significance	Brugada syndrome 5	2022-07-19	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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 190862). This variant has not been reported in the literature in individuals affected with SCN1B-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 123 of the SCN1B protein (p.Val123Ile).
Ambry Genetics	RCV002453586	SCV002615259	likely benign	Cardiovascular phenotype	2024-02-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.