Submissions for variant NM_001365999.1(SZT2):c.2812G>A (p.Ala938Thr)

gnomAD frequency: 0.00033  dbSNP: rs143880787

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805074	SCV000945017	uncertain significance	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 938 of the SZT2 protein (p.Ala938Thr). This variant is present in population databases (rs143880787, gnomAD 0.05%). This missense change has been observed in individual(s) with Rolandic epilepsy (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 433087). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199346	SCV001370432	uncertain significance	Developmental and epileptic encephalopathy, 18	2019-07-19	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP5.
CeGaT Center for Human Genetics Tuebingen	RCV000805074	SCV001371259	uncertain significance	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001199346	SCV001522667	uncertain significance	Developmental and epileptic encephalopathy, 18	2020-09-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000805074	SCV001779759	uncertain significance	not provided	2025-02-27	criteria provided, single submitter	clinical testing	Observed in a patient with childhood focal epilepsy with centro-temporal spikes through whole exome sequencing, however, a second SZT2 variant was not reported (PMID: 29358611); 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: 29358611)
Genome-Nilou Lab	RCV001199346	SCV004180756	uncertain significance	Developmental and epileptic encephalopathy, 18	2023-04-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004797822	SCV005419385	uncertain significance	See cases	2024-09-06	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PP3
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000655970	SCV000588246	pathogenic	Self-limited epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15
PreventionGenetics, part of Exact Sciences	RCV004748789	SCV005361115	uncertain significance	SZT2-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The SZT2 c.2812G>A variant is predicted to result in the amino acid substitution p.Ala938Thr. This variant was reported as a single heterozygote in an individual with Rolandic epilepsy (Bobbili et al. 2018. PubMed ID: 29358611, Supplemental Table 1); however, no additional information was provided to support causation. This variant is reported in 0.044% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is more common than expected for a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.