ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.5113T>A (p.Phe1705Ile) (rs1064794243)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484046 SCV000568351 likely pathogenic not provided 2017-02-03 criteria provided, single submitter clinical testing A F1705I variant that is likely pathogenic has been identified in the SCN4A gene. The F17051 has been reported, along with a benign polymorphism (T323M), in an individual with muscle stiffness and cramps and clinical diagnosis of myotonia and a. Functional analysis showed that F1705I disrupted fast inactivation, a defect that is commonly observed in myotonia. The T323M polymorphism did not disrupt channel kinetics as compared to wildtype (Wu et al., 2005). The F1705I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the F1705I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Athena Diagnostics Inc RCV000484046 SCV000615109 pathogenic not provided 2021-06-02 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations ( This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant leads to impaired SCN4A channel activity (PMID: 15774523, 18690054, 24324661). Computational tools predict that this variant is damaging.
Invitae RCV000654650 SCV000776546 uncertain significance Familial hyperkalemic periodic paralysis 2019-07-02 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 1705 of the SCN4A protein (p.Phe1705Ile). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with myotonia (PMID: 15774523). ClinVar contains an entry for this variant (Variation ID: 420020). Experimental studies have shown that this missense change impacts SCN4A channel activity and function (PMID: 15774523, 24324661, 18690054). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000484046 SCV001248150 pathogenic not provided 2017-07-01 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.