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

dbSNP: rs796052492

Total submissions: 3

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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816542	SCV000957057	uncertain significance	Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4	2022-11-15	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Leu267 amino acid residue in GABRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 205521). This missense change has been observed in individual(s) with clinical features of GABRA1-related conditions (PMID: 28837158). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 267 of the GABRA1 protein (p.Leu267Ile).
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477826	SCV000536726	likely pathogenic	Epilepsy, idiopathic generalized, susceptibility to, 13; Developmental and epileptic encephalopathy, 19	2016-12-12	no assertion criteria provided	research