ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr) (rs796053162)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189176 SCV000242808 likely pathogenic not provided 2013-07-18 criteria provided, single submitter clinical testing p.Ala1773Thr (GCG>ACG): c.5317 G>A in exon 27 of the SCN2A gene (NM_021007.2). The Ala1773Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a non-polar Alanine residue is replaced by a polar Threonine residue. It alters a highly conserved position in the S6 segment of the fourth transmembrane domain of the protein, and multiple in silico algorithms predict it may be damaging to protein structure/function. Therefore, based on the currently available information, Ala1773Thr is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Invitae RCV000524506 SCV000551877 likely pathogenic Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1773 of the SCN2A protein (p.Ala1773Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with SCN2A-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207024). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000622944 SCV000741215 likely pathogenic Inborn genetic diseases 2015-12-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
CeGaT Praxis fuer Humangenetik Tuebingen RCV000189176 SCV001152490 likely pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001250742 SCV001426159 likely pathogenic Early infantile epileptic encephalopathy 11 2018-05-14 criteria provided, single submitter clinical testing

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