Submissions for variant NM_006514.4(SCN10A):c.3674T>C (p.Ile1225Thr)

gnomAD frequency: 0.00048  dbSNP: rs139638446

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514921	SCV000610656	likely benign	not provided	2017-07-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000603074	SCV000730434	likely benign	not specified	2017-12-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087793	SCV000760266	likely benign	Brugada syndrome	2025-01-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000987251	SCV001136501	benign	Brugada syndrome 1	2023-08-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002455988	SCV002615858	likely benign	Cardiovascular phenotype	2018-12-03	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.
CeGaT Center for Human Genetics Tuebingen	RCV000514921	SCV004154208	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	SCN10A: BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000603074	SCV005883342	likely benign	not specified	2024-12-17	criteria provided, single submitter	clinical testing	Variant summary: SCN10A c.3674T>C (p.Ile1225Thr) 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 0.00049 in 1614116 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 78 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN10A causing Arrhythmia phenotype (6.3e-06). At-least one study has described that p.Ile1225Thr could be a genetic modifiers of the J-point and QTc interval (Ghouse_2017). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. The following publication has been ascertained in the context of this evaluation (PMID: 27711072). ClinVar contains an entry for this variant (Variation ID: 445871). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004541599	SCV004799559	likely benign	SCN10A-related disorder	2023-09-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).