Submissions for variant NM_174934.4(SCN4B):c.18C>A (p.Asp6Glu)

gnomAD frequency: 0.00019  dbSNP: rs149979176

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001698986	SCV000223636	uncertain significance	not provided	2023-11-27	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868)
Ambry Genetics	RCV000619472	SCV000735544	likely benign	Cardiovascular phenotype	2024-08-05	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216410	SCV001388207	uncertain significance	Long QT syndrome 10	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 6 of the SCN4B protein (p.Asp6Glu). This variant is present in population databases (rs149979176, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SCN4B-related conditions. ClinVar contains an entry for this variant (Variation ID: 190889). 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 tolerated. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001216410	SCV003920436	uncertain significance	Long QT syndrome 10		criteria provided, single submitter	clinical testing	SCN4B NM_174934.3 exon 1 p.Asp6Glu (c.18C>A): This variant has not been reported in the literature but is present in 0.02% (30/124990) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-118023371-G-T). This variant is present in ClinVar (Variation ID:190889). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005406881	SCV006072337	likely benign	not specified	2025-03-07	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001698986	SCV001922696	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001698986	SCV001927453	likely benign	not provided		no assertion criteria provided	clinical testing