ClinVar Miner

Submissions for variant NM_001127644.2(GABRA1):c.799C>A (p.Leu267Ile) (rs796052492)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187500 SCV000241094 likely pathogenic not provided 2012-07-02 criteria provided, single submitter clinical testing p.Leu267Ile (CTC>ATC): c.799 C>A in exon 9 of the GABRA1 gene (NM_000806.5). The Leu267Ile missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Leu267Ile in approximately 5,000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative, as Leucine and Isoleucine are both uncharged, non-polar amino acids. However, it alters a position in the first transmembrane domain that is highly conserved across species and in related proteins. Several in silico algorithms predict Leu267Ile is likely damaging to protein structure/function, while another predicts it is likely not pathogenic. Therefore, based on the currently available information, it is unclear whether Leu267Ile is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000816542 SCV000957057 uncertain significance Idiopathic generalized epilepsy; Epilepsy, juvenile myoclonic 5; Epilepsy, childhood absence 4 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 267 of the GABRA1 protein (p.Leu267Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GABRA1-related disease. ClinVar contains an entry for this variant (Variation ID: 205521). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477826 SCV000536726 likely pathogenic Epilepsy, juvenile myoclonic 5; Epileptic encephalopathy, early infantile, 19 2016-12-12 no assertion criteria provided research

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