ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000484046 SCV000615109 likely pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing
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.
Invitae RCV000654650 SCV000776546 uncertain significance Hyperkalemic Periodic Paralysis Type 1 2018-06-22 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.

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