Submissions for variant NM_001365999.1(SZT2):c.7474C>T (p.Arg2492Trp)

gnomAD frequency: 0.00007  dbSNP: rs373062274

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002317600	SCV000851160	uncertain significance	Inborn genetic diseases	2017-12-27	criteria provided, single submitter	clinical testing	The p.R2435W variant (also known as c.7303C>T), located in coding exon 52 of the SZT2 gene, results from a C to T substitution at nucleotide position 7303. The arginine at codon 2435 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been described in an individual with early onset epileptic encephalopathy who was compound heterozygous for another missense alteration (Tshuchida N et al. Clin. Genet., 2017 May; epub ahead of print). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000981751	SCV001129747	likely benign	not provided	2024-01-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000981751	SCV002504457	likely benign	not provided	2020-04-07	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Revvity Omics, Revvity	RCV001292588	SCV003818883	uncertain significance	Developmental and epileptic encephalopathy, 18	2022-01-18	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001292588	SCV005087241	uncertain significance	Developmental and epileptic encephalopathy, 18	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 18 (MIM#615476). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (89 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.(Arg2435Gln)) has been reported as a VUS (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely benign, and as a VUS (ClinVar, LOVD). It has also been observed in a single compound heterozygous individual with features including tonic spasms, microcephaly and early onset epileptic encephalopathy (PMID: 28556953). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV001292588	SCV001481161	pathogenic	Developmental and epileptic encephalopathy, 18	2021-02-19	no assertion criteria provided	literature only