ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.1739G>A (p.Arg580Gln) (rs544692790)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000710209 SCV000203513 uncertain significance not provided 2014-01-22 criteria provided, single submitter clinical testing
GeneDx RCV000710209 SCV000242508 uncertain significance not provided 2018-04-24 criteria provided, single submitter clinical testing The Arg580Gln missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved through mammals but is not conserved in more distant species through evolution in the cytoplasmic loop between the first and second homologous domains. Multiple in silico algorithms predict it may be damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether Arg580Gln is a pathogenic variant or a rare benign variant.
Invitae RCV000471353 SCV000548756 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2018-05-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 580 of the SCN1A protein (p.Arg580Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs544692790, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 167646). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). 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. This variant identified in the SCN1A gene is located in the DI/DII cytoplasmic linker region of the resulting protein (PMID: 18804930, 25348405), but it is unclear how this variant impacts the function of this protein.
Fulgent Genetics,Fulgent Genetics RCV000515440 SCV000611518 uncertain significance Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2017-05-23 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710209 SCV000615025 likely benign not provided 2018-08-31 criteria provided, single submitter clinical testing

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