Submissions for variant NM_006514.4(SCN10A):c.3474C>G (p.Ile1158Met)

gnomAD frequency: 0.00002  dbSNP: rs145568435

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV001508501	SCV001714702	uncertain significance	not provided	2019-09-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001508501	SCV001790551	uncertain significance	not provided	2019-11-25	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861437	SCV002301972	uncertain significance	Brugada syndrome	2022-06-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1158 of the SCN10A protein (p.Ile1158Met). This variant is present in population databases (rs145568435, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 373688). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN10A protein function. 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.
Ambry Genetics	RCV002460071	SCV002618466	likely benign	Cardiovascular phenotype	2021-03-03	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.
Fulgent Genetics, Fulgent Genetics	RCV002481284	SCV002784269	uncertain significance	Episodic pain syndrome, familial, 2	2021-08-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000412880	SCV000492304	uncertain significance	not specified	2016-12-06	flagged submission	clinical testing	A variant of uncertain significance has been identified in the SCN10A gene. The I1158M variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in both the Exome Aggregation Consortium and 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. Additionally, in silico analysis predicts the I1158M variant is probably damaging to the protein structure/function. Nevertheless, this variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and it occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.