Submissions for variant NM_001349253.2(SCN11A):c.4282G>A (p.Gly1428Ser)

gnomAD frequency: 0.00012  dbSNP: rs201336927

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000651878	SCV000773734	uncertain significance	Hereditary sensory and autonomic neuropathy type 7; Familial episodic pain syndrome with predominantly lower limb involvement	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1428 of the SCN11A protein (p.Gly1428Ser). This variant is present in population databases (rs201336927, gnomAD 0.04%), 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: 30554136). ClinVar contains an entry for this variant (Variation ID: 541573). 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 not expected to disrupt SCN11A protein function with a negative 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.
GeneDx	RCV001556793	SCV001778433	likely benign	not provided	2019-03-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002331260	SCV002627861	likely benign	Inborn genetic diseases	2019-09-06	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488766	SCV004241151	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: SCN11A c.4282G>A (p.Gly1428Ser) 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 0.00021 in 250742 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SCN11A, allowing no conclusion about variant significance. c.4282G>A has been reported in the literature in individuals affected with clinical features of SCN11A-related conditions (e.g., Eijkenboom_2018, Valentino_2021). However, these data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30554136, 34356170). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified the variant as likely benign, while one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genetics, Academic Medical Center	RCV001556793	SCV001923042	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001556793	SCV001953801	uncertain significance	not provided		no assertion criteria provided	clinical testing