Submissions for variant NM_007327.4(GRIN1):c.1643G>A (p.Arg548Gln)

dbSNP: rs1554770044

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000622458	SCV000741802	pathogenic	Inborn genetic diseases	2016-09-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001591400	SCV001824079	pathogenic	not provided	2022-05-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29720203)
3billion	RCV002051870	SCV002318515	pathogenic	Intellectual disability, autosomal dominant 8	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521298, PMID:29720203). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29720203). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV002051870	SCV003459882	uncertain significance	Intellectual disability, autosomal dominant 8	2022-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 548 of the GRIN1 protein (p.Arg548Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GRIN1-related conditions (PMID: 29720203). ClinVar contains an entry for this variant (Variation ID: 521298). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GRIN1 protein function. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV002051870	SCV004047152	pathogenic	Intellectual disability, autosomal dominant 8		criteria provided, single submitter	clinical testing	The missense variant c.1643G>A (p.Arg548Gln) in GRIN1 gene has been reported in a de novo heterozygous state in individuals affected with severe childhood epilepsy (Staněk D. et al., 2018). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as Pathogenic. The amino acid Arginine at position 548 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV002051870	SCV004801564	likely pathogenic	Intellectual disability, autosomal dominant 8	2019-01-15	criteria provided, single submitter	clinical testing	The GRIN1 c.1706G>A p.(Arg569Gln) missense variant, to our knowledge, has not been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. This variant was identified in a de novo state in the proband. Based on the available evidence, the c.1706G>A p.(Arg569Gln) variant is classified as likely pathogenic for autosomal dominant intellectual disability.