Submissions for variant NM_006514.4(SCN10A):c.1977T>G (p.Phe659Leu)

dbSNP: rs1346592471

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001901192	SCV002162681	uncertain significance	Brugada syndrome	2021-04-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine with leucine at codon 659 of the SCN10A protein (p.Phe659Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN10A-related conditions. 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 not 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	RCV002422993	SCV002722715	uncertain significance	Cardiovascular phenotype	2021-07-11	criteria provided, single submitter	clinical testing	The p.F659L variant (also known as c.1977T>G), located in coding exon 13 of the SCN10A gene, results from a T to G substitution at nucleotide position 1977. The phenylalanine at codon 659 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987931	SCV004804035	uncertain significance	not specified	2024-01-03	criteria provided, single submitter	clinical testing	Variant summary: SCN10A c.1977T>G (p.Phe659Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-06 in 1456118 control chromosomes (i.e. 14 carriers) in the gnomAD database (v4.0 dataset). The relatively high number of carriers suggests that the variant is likely not associated with a dominant, severe and penetrant disease phenotype. To our knowledge, no occurrence of c.1977T>G in individuals affected with SCN10A-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.