Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000210655 | SCV000262840 | pathogenic | Inborn genetic diseases | 2020-03-04 | criteria provided, single submitter | clinical testing | The p.N614S pathogenic mutation (also known as c.1841A>G), located in coding exon 8 of the GRIN2A gene, results from an A to G substitution at nucleotide position 1841. The asparagine at codon 614 is replaced by serine, an amino acid with highly similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of developmental delay (Farwell KD et al. Genet. Med., 2015 Jul;17:578-86). In addition, this mutation has been detected as de novo occurrences in four additional individuals who all had severe intellectual disability/developmental delay. Other symptoms in some, but not all of these individuals included epilepsy, hypotonia, ataxia, and hand stereotypies (von Stülpnagel C et al. Eur. J. Paediatr. Neurol., 2017 May;21:530-541; Møller RS et al. Mol Syndromol, 2016 Sep;7:210-219; Strehlow V et al. Brain, 2019 01;142:80-92). In one functional study, authors evaluated the receptor cell surface expression, pharmacological properties, and biophysical characteristics of this alteration and found reduced proton sensitivity compared to wild type receptors, reduced current amplitude to prolonged application of glutamate and glycine, and showed a significant reduction of surfacetototal protein level, which reflects receptor trafficking efficiency (Li J et al. Hum. Mutat., 2019 12;40:2393-2413). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Baylor Genetics | RCV001330044 | SCV001521635 | pathogenic | Landau-Kleffner syndrome | 2019-09-13 | criteria provided, single submitter | clinical testing | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported multiple times both in the literature and internally as disease-causing [PMID: 25356970, ClinVar ID: 224990] |
| Institute of Human Genetics, |
RCV001330044 | SCV002026444 | likely pathogenic | Landau-Kleffner syndrome | 2019-01-01 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV001330044 | SCV003443488 | pathogenic | Landau-Kleffner syndrome | 2022-03-18 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects GRIN2A function (PMID: 31429998). For these reasons, this variant has been classified as Pathogenic. 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 GRIN2A protein function. ClinVar contains an entry for this variant (Variation ID: 224990). This missense change has been observed in individual(s) with clinical features of GRIN2A-related conditions (PMID: 25356970, 28109652, 30544257). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 614 of the GRIN2A protein (p.Asn614Ser). |