ClinVar Miner

Submissions for variant NM_001134407.3(GRIN2A):c.1123G>A (p.Val375Met)

gnomAD frequency: 0.00001  dbSNP: rs746834456
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480663 SCV000573697 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the GRIN2A gene. The V375M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V375M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V375M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, 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 variant or a rare benign variant.
Invitae RCV001368694 SCV001565100 uncertain significance Landau-Kleffner syndrome 2023-03-01 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 375 of the GRIN2A protein (p.Val375Met). This variant is present in population databases (rs746834456, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GRIN2A-related conditions. This missense change has been observed in at least one individual who was not affected with GRIN2A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 423933). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. 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.

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