ClinVar Miner

Submissions for variant NM_006514.4(SCN10A):c.3675T>G (p.Ile1225Met)

gnomAD frequency: 0.00008  dbSNP: rs371834340
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000638675 SCV000760214 uncertain significance Brugada syndrome 2024-09-06 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 1225 of the SCN10A protein (p.Ile1225Met). This variant is present in population databases (rs371834340, gnomAD 0.008%). This missense change has been observed in individual(s) with sudden cardiac arrest (PMID: 30975432). ClinVar contains an entry for this variant (Variation ID: 532074). 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 RCV002343249 SCV002619145 likely benign Cardiovascular phenotype 2019-09-05 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.
GeneDx RCV004723011 SCV005332539 uncertain significance not provided 2023-06-01 criteria provided, single submitter clinical testing Identified in an individual with history of sudden cardiac arrest who also harbored other cardiogenetic variant(s) (Asatryan et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30975432)
Mayo Clinic Laboratories, Mayo Clinic RCV004723011 SCV005409170 uncertain significance not provided 2024-03-19 criteria provided, single submitter clinical testing BS2

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