ClinVar Miner

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

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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 RCV000724565 SCV000227215 uncertain significance not provided 2015-03-12 criteria provided, single submitter clinical testing
GeneDx RCV000724565 SCV000242461 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN1A gene. The H127D variant in the SCN1A gene has been reported previously 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 that same paper, H127D was identified in another individual with classic Dravet syndrome who had another missense variant (P1451S) in SCN1A (Zuberi et al., 2011). The H127D variant is observed in 18/126,234 (0.014%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The H127D variant 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 is predicted to be within the transmembrane segment S1 of the first homologous domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
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

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