ClinVar Miner

Submissions for variant NM_001127644.2(GABRA1):c.1130C>T (p.Pro377Leu)

gnomAD frequency: 0.00002  dbSNP: rs751571034
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187507 SCV000241101 uncertain significance not provided 2016-02-29 criteria provided, single submitter clinical testing The P377L variant 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. This substitution occurs at a position that is conserved across species. The P377L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant
New York Genome Center RCV001256040 SCV001432825 uncertain significance Seizure 2019-12-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001852457 SCV002202625 uncertain significance Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4 2021-08-05 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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 205528). This variant has not been reported in the literature in individuals affected with GABRA1-related conditions. This variant is present in population databases (rs751571034, ExAC 0.009%). This sequence change replaces proline with leucine at codon 377 of the GABRA1 protein (p.Pro377Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
Ambry Genetics RCV002321754 SCV002610466 likely benign Inborn genetic diseases 2018-02-28 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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