ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4760A>T (p.Tyr1587Phe) (rs377325221)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188979 SCV000242610 likely pathogenic not provided 2015-07-06 criteria provided, single submitter clinical testing p.Tyr1598Phe (TAT>TTT): c.4793 A>T in exon 25 of the SCN1A gene (NM_001165963.1) The Y1598F variant was previously reported in an external mutation database in an association with GEFS+, however more detailed information about inheritance was not provided. The Y1598F variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. It 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 alters a highly conserved position predicted to be within the intracellular loop between the S2 and S3 transmembrane segments of the fourth homologous domain. Additionally, multiple missense mutations in nearby residues have been reported in association with SCN1A-related disorders, supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Ambry Genetics RCV000720187 SCV000851064 uncertain significance History of neurodevelopmental disorder 2016-06-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188979 SCV000863017 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing
Invitae RCV000812724 SCV000953047 uncertain significance Early infantile epileptic encephalopathy 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with phenylalanine at codon 1598 of the SCN1A protein (p.Tyr1598Phe). The tyrosine residue is highly conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is present in population databases (rs377325221, ExAC 0.002%). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 206850). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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