Submissions for variant NM_020699.4(GATAD2B):c.1241G>A (p.Arg414Gln)

dbSNP: rs1057521041

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433516	SCV000520738	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31949314)
Mendelics	RCV000986415	SCV001135414	pathogenic	Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000986415	SCV004050291	likely pathogenic	Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome	2023-04-11	criteria provided, single submitter	clinical testing
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV000986415	SCV004190171	likely pathogenic	Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome	2021-08-17	criteria provided, single submitter	clinical testing	The c.1241G>A variant is a heterozygous single base pair substitution at nucleotide 1241 in exon 8 of 11 of the GATAD2B gene, resulting in a substitution of a highly conserved arginine at amino acid position 414 to a glutamine (p.Arg414Gln). This variant is absent from the gnomAD database, indicating it is not a common benign occurrence in the populations represented in these databases. In silico predictors are inconsistent in predicting an effect on the structure and/or function of the protein (benign by PolyPhen2, tolerated by SIFT, disease causing by MutationTaster). The GATAD2B gene encodes GATA zinc finger domain-containing protein 2B, a subunit of the NuRD complex. The NuRD complex is an important regulator of gene expression with both histone deacetylase and chromatin remodeling activity. The arginine at position 414 falls in the CR2 conserved region, which contains a GATA-type zinc finger motif (PMID: 11756549) and is known to interact with other NuRD proteins. The p.Arg414Gln variant has been previously reported as de novo in two unrelated individuals with intellectual disability associated with expressive and receptive language issues (PMID: 31949314). Immunoprecipitation assays utilizing in vitro transcription-translation products revealed that the p.Arg414Gln variant causes a mild reduction in the interactions with CHD paralogues, disrupting assembly of NuRD complex proteins (PMID: 31949314).
CeGaT Center for Human Genetics Tuebingen	RCV000433516	SCV004704292	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	GATAD2B: PM2, PM6, PS4:Moderate, PP3, PS3:Supporting
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000986415	SCV005399014	pathogenic	Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with GAND syndrome (MIM#615074). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated CR2 domain (PMID: 31949314). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed as de novo in two unrelated individuals with GAND syndrome (PMID: 31949314). (SP) 1010 - Functional evidence for this variant is inconclusive. Co-expression and pulldown experiments showed a mild reduction in CHD binding (PMID: 31949314). (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000986415	SCV001439212	pathogenic	Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome	2020-10-22	no assertion criteria provided	literature only