ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.379C>G (p.His127Asp) (rs148442069)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD, LLC RCV000724565 SCV000227215 uncertain significance not provided 2015-03-12 criteria provided, single submitter clinical testing
GeneDx RCV000724565 SCV000242461 uncertain significance not provided 2021-05-24 criteria provided, single submitter clinical testing Reported as a de novo change in an individual with clinical features of borderline Dravet syndrome; however, paternity was not established (Zuberi et al., 2011). In the same paper, H127D was identified in another individual with classic Dravet syndrome who had another missense variant (P1451S) in SCN1A (Zuberi et al., 2011).; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This substitution is predicted to be in the N-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 32090326, 29655203, 28202706, 28150151, 21248271, 20831750)
Invitae RCV000474474 SCV000548782 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 127 of the SCN1A protein (p.His127Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs148442069, ExAC 0.01%). This variant has been reported in individuals with Dravet syndrome or febrile seizures (PMID: 21248271, 28202706). In one of these individuals, the variant was determined to be de novo. ClinVar contains an entry for this variant (Variation ID: 195131). 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: "Benign"; Align-GVGD: "Class C65"). This variant disrupts the p.His127 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 27465585), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Fulgent Genetics,Fulgent Genetics RCV000764287 SCV000895306 uncertain significance Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000724565 SCV001739893 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000724565 SCV001957154 uncertain significance not provided no assertion criteria provided clinical testing

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