Submissions for variant NM_001365999.1(SZT2):c.9629G>A (p.Arg3210His)

gnomAD frequency: 0.00004  dbSNP: rs371193436

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000983878	SCV001131921	likely benign	not provided	2024-10-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000983878	SCV001772855	uncertain significance	not provided	2019-07-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV002254328	SCV002525524	uncertain significance	Developmental and epileptic encephalopathy, 18	2022-03-17	criteria provided, single submitter	clinical testing	The c.9458G>A variant is present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and Indian Exome Database at a low frequency. The variant was previously in reported to ClinVar (Accession: VCV000800214.5), with conflicting interpretations of pathogenicity (likely benign/uncertain significance). In-silico pathogenicity prediction programs like PolyPhen-2, MutationTaster2, CADD etc. predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies.
Ambry Genetics	RCV002372702	SCV002688310	uncertain significance	Inborn genetic diseases	2017-12-27	criteria provided, single submitter	clinical testing	The p.R3153H variant (also known as c.9458G>A), located in coding exon 68 of the SZT2 gene, results from a G to A substitution at nucleotide position 9458. The arginine at codon 3153 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV002254328	SCV003818882	uncertain significance	Developmental and epileptic encephalopathy, 18	2022-07-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002254328	SCV004049348	likely benign	Developmental and epileptic encephalopathy, 18	2023-04-11	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV002254328	SCV005382359	uncertain significance	Developmental and epileptic encephalopathy, 18	2023-05-20	criteria provided, single submitter	clinical testing	The missense variant c.9629G>A (p.Arg3210His) in the SZT2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.02%) in the gnomAD Exomes and absent in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance/ Likely benign. However, no details are available for independent assessment. The amino acid Arginine at position 3210 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg3210His in SZT2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.