Submissions for variant NM_006514.4(SCN10A):c.4831G>A (p.Gly1611Arg)

gnomAD frequency: 0.00007  dbSNP: rs777980971

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623531	SCV000740407	uncertain significance	not specified	2017-05-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001231916	SCV001404454	uncertain significance	Brugada syndrome	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1611 of the SCN10A protein (p.Gly1611Arg). This variant is present in population databases (rs777980971, gnomAD 0.007%). 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: 520456). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN10A protein function with a positive predictive value of 80%. 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	RCV002334032	SCV002635096	uncertain significance	Cardiovascular phenotype	2024-03-17	criteria provided, single submitter	clinical testing	The p.G1611R variant (also known as c.4831G>A), located in coding exon 27 of the SCN10A gene, results from a G to A substitution at nucleotide position 4831. The glycine at codon 1611 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
GeneDx	RCV002461932	SCV002757016	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002483741	SCV002792489	uncertain significance	Episodic pain syndrome, familial, 2	2022-02-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000623531	SCV005040379	uncertain significance	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: SCN10A c.4831G>A (p.Gly1611Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251252 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4831G>A in individuals affected with SCN10A-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 520456). Based on the evidence outlined above, the variant was classified as uncertain significance.