Submissions for variant NM_006514.4(SCN10A):c.5024C>T (p.Pro1675Leu)

gnomAD frequency: 0.00002  dbSNP: rs564943632

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067815	SCV001232896	uncertain significance	Brugada syndrome	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1675 of the SCN10A protein (p.Pro1675Leu). This variant is present in population databases (rs564943632, gnomAD 0.1%). 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: 861312). 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 95%. 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	RCV003307918	SCV004000505	benign	Cardiovascular phenotype	2023-04-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782638	SCV005395774	uncertain significance	not specified	2024-09-04	criteria provided, single submitter	clinical testing	Variant summary: SCN10A c.5024C>T (p.Pro1675Leu) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251188 control chromosomes. The observed variant frequency is approximately 11.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN10A causing Arrhythmia phenotype (6.3e-06), suggesting the variant could be benign. To our knowledge, c.5024C>T has not been reported in the literature in individuals affected with Arrhythmia and no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 861312). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.