Submissions for variant NM_001365999.1(SZT2):c.2888A>G (p.Lys963Arg)

gnomAD frequency: 0.00025  dbSNP: rs144176855

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000713741	SCV000553343	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 963 of the SZT2 protein (p.Lys963Arg). This variant is present in population databases (rs144176855, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with SZT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411928). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SZT2 protein function. 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.
Athena Diagnostics Inc	RCV000713741	SCV000844370	uncertain significance	not provided	2017-09-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002523407	SCV003725501	uncertain significance	Inborn genetic diseases	2021-10-18	criteria provided, single submitter	clinical testing	The c.2888A>G (p.K963R) alteration is located in exon 20 (coding exon 20) of the SZT2 gene. This alteration results from a A to G substitution at nucleotide position 2888, causing the lysine (K) at amino acid position 963 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230505	SCV003928421	uncertain significance	not specified	2023-04-21	criteria provided, single submitter	clinical testing	Variant summary: C1orf84 c.2888A>G (p.Lys963Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 282858 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2888A>G in individuals affected with Early Infantile Epileptic Encephalopathy 18 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV003457683	SCV004180800	uncertain significance	Developmental and epileptic encephalopathy, 18	2023-04-11	criteria provided, single submitter	clinical testing