Submissions for variant NM_007327.4(GRIN1):c.1858G>C (p.Gly620Arg)

dbSNP: rs797045047

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191091	SCV000245488	likely pathogenic	Intellectual disability, autosomal dominant 8	2014-10-21	criteria provided, single submitter	clinical testing	Likely pathogenicity based on finding it twice in our laboratory de novo: in a 24-year-old female with absent speech, autism, intellectual disability, mild unilateral conductive hearing loss, spasticity, joint laxity, failure to thrive, gastroesophageal disorder, strabismus, myopia, mild mitral valve prolapse, intermittent episodes of syncope, and scoliosis; in a 7-year-old male with absent speech, regression, intellectual disability, congenital hypotonia, movement disorder, short stature
GeneDx	RCV000479068	SCV000569832	pathogenic	not provided	2023-01-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: loss of NMDA receptor function (Lemke et al., 2016; Chen et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27164704, 26633545, 28228639, 31487502, 31429998)
Ambry Genetics	RCV000622498	SCV000742522	likely pathogenic	Inborn genetic diseases	2018-12-24	criteria provided, single submitter	clinical testing	The p.G620R variant (also known as c.1858G>C), located in coding exon 13 of the GRIN1 gene, results from a G to C substitution at nucleotide position 1858. The glycine at codon 620 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in individuals with intellectual disability and has been shown to have an impact on protein function (Lemke JR et al. Neurology, 2016 06;86:2171-8; Chen W et al. J. Hum. Genet., 2017 Jun;62:589-597). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with global developmental delay and hypotonia (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526577	SCV001737004	pathogenic	Seizure		criteria provided, single submitter	research
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000479068	SCV002051694	pathogenic	not provided	2021-01-19	criteria provided, single submitter	clinical testing	PS3, PP2, PP3, PM1, PM2, PS4_Moderate
Labcorp Genetics (formerly Invitae), Labcorp	RCV000191091	SCV002240115	pathogenic	Intellectual disability, autosomal dominant 8	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 620 of the GRIN1 protein (p.Gly620Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant GRIN1-related conditions (PMID: 28228639, 34884460). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 209159). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GRIN1 protein function. Experimental studies have shown that this missense change affects GRIN1 function (PMID: 28228639, 31429998). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000479068	SCV002498081	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	GRIN1: PS2, PM1, PM2, PP2, PP3, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000191091	SCV002511789	pathogenic	Intellectual disability, autosomal dominant 8	2022-04-16	criteria provided, single submitter	clinical testing	Variant summary: GRIN1 c.1858G>C (p.Gly620Arg) results in a non-conservative amino acid change located in the Ionotropic glutamate receptor domain (IPR001320) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244402 control chromosomes. c.1858G>C has been reported in the literature as a de-novo variant in multiple individuals affected with features of Autosomal Dominant Neurodevelopmental Disorder With Or Without Hyperkinetic Movements And Seizures (example, Chen_2017, Lemke_2016, Costain_2019, Li_2019, Santos-Gomez_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting a reduction in N-methyl-D-aspartate (NMDAR) receptor trafficking, expression and function (example, Chen_2017). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000191091	SCV000678284	pathogenic	Intellectual disability, autosomal dominant 8	2022-03-28	no assertion criteria provided	literature only