ClinVar Miner

Submissions for variant NM_001349253.2(SCN11A):c.2095G>A (p.Gly699Arg)

gnomAD frequency: 0.00009  dbSNP: rs145734191
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000706069 SCV000835100 uncertain significance Hereditary sensory and autonomic neuropathy type 7; Familial episodic pain syndrome with predominantly lower limb involvement 2025-01-23 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 699 of the SCN11A protein (p.Gly699Arg). This variant is present in population databases (rs145734191, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with small fiber neuropathy (PMID: 25791876). ClinVar contains an entry for this variant (Variation ID: 582088). 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 SCN11A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SCN11A function (PMID: 25791876). 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.
Mayo Clinic Laboratories, Mayo Clinic RCV001509214 SCV001715814 uncertain significance not provided 2022-02-22 criteria provided, single submitter clinical testing
GeneDx RCV001509214 SCV001791785 uncertain significance not provided 2021-01-13 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (enhanced sodium channel activation, slowed fast inactivation, and increased neuronal excitability) (Han et al., 2015); This variant is associated with the following publications: (PMID: 25791876)
Ambry Genetics RCV002422607 SCV002730326 likely benign Inborn genetic diseases 2021-02-09 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.
Revvity Omics, Revvity RCV001509214 SCV003820691 uncertain significance not provided 2021-01-05 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000790193 SCV000929585 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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