ClinVar Miner

Submissions for variant NM_000834.5(GRIN2B):c.2627C>T (p.Ala876Val)

gnomAD frequency: 0.00001  dbSNP: rs1458368988
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital RCV001732135 SCV001984040 uncertain significance Developmental and epileptic encephalopathy, 27 2020-07-21 criteria provided, single submitter clinical testing
New York Genome Center RCV001836996 SCV002097910 uncertain significance Intellectual disability, autosomal dominant 6; Developmental and epileptic encephalopathy, 27 2021-02-09 criteria provided, single submitter clinical testing The inherited c.2627C>T, p.Ala876Val missense variant identified in GRIN2B has not been reported in the literature. This variant has two heterozygotes in the gnomAD v3.1database, indicating this is a rare allele. In silico analysis predicts conflicting interpretation of pathogenicity [PMID:27268795] and the position is not strongly conserved (GERP++ = 5.3). Based on the available evidence, the inherited missense variant c.2627C>T, p.Ala876Val in the GRIN2B gene is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001836996 SCV003263794 benign Intellectual disability, autosomal dominant 6; Developmental and epileptic encephalopathy, 27 2024-12-24 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356519 SCV001551716 uncertain significance not provided no assertion criteria provided clinical testing The GRIN2B p.Ala876Val variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs1458368988) and in Cosmic (FATHMM prediction: pathogenic; score=0.95). The variant was identified in control databases in 5 of 280346 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: Latino in 4 of 35420 chromosomes (freq: 0.000113) and European (non-Finnish) in 1 of 127558 chromosomes (freq: 0.000008), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ala876 residue is conserved in mammals but not in more distantly related organisms however computational analyses (SIFT, AlignGVGD, BLOSUM, PolyPhen-2, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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