ClinVar Miner

Submissions for variant NM_007327.4(GRIN1):c.2530C>T (p.Arg844Cys) (rs1554770667)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623606 SCV000741889 pathogenic Inborn genetic diseases 2016-10-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000730546 SCV000858291 likely pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763192 SCV000893804 likely pathogenic Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001043920 SCV001207689 pathogenic Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant 2020-02-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 844 of the GRIN1 protein (p.Arg844Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with epileptic encephalopathy (PMID: 27159321, 30776697, 27164704). In at least one individual the variant was observed to be de novo. This variant is also known as c.2593C>T (p.Arg865Cys) in the literature. ClinVar contains an entry for this variant (Variation ID: 521354). This variant has been reported to have conflicting or insufficient data to determine the effect on GRIN1 protein function (PMID: 27164704). For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV001043920 SCV001251875 likely pathogenic Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant 2020-05-03 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Strasbourg University Hospital RCV001260636 SCV001437728 likely pathogenic Intellectual disability 2020-09-10 criteria provided, single submitter clinical testing
GeneDx RCV000730546 SCV001766813 pathogenic not provided 2020-09-14 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (increased and prolonged calcium influx in cortical neurons) (Furuse et al., 2010); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29124671, 30945278, 23688147, 20345915, 27164704, 27159321, 30776697)
Clinical Genomics Program, Stanford Medicine RCV001043920 SCV001427060 pathogenic Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant 2019-05-29 no assertion criteria provided clinical testing The p.Arg844Cys variant in the GRIN1 gene has been previously reported de novo in 4 individuals with features consistent with GRIN1-associated neurodevelopmental disorder (Lemke et al., 2016; Vanderver et al., 2016; Wang et al., 2019). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The GRIN1 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that the p.Arg844Cys is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg844Cys variant as pathogenic for autosomal dominant GRIN1-associated neurodevelopmental disorder based on the information above. [ACMG evidence codes used: PS2_VeryStrong; PM2; PP2; PP3]

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