ClinVar Miner

Submissions for variant NM_001365999.1(SZT2):c.2228A>G (p.His743Arg)

gnomAD frequency: 0.00013  dbSNP: rs545593466
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002318096 SCV000849779 uncertain significance Inborn genetic diseases 2023-05-24 criteria provided, single submitter clinical testing The c.2228A>G (p.H743R) alteration is located in exon 15 (coding exon 15) of the SZT2 gene. This alteration results from a A to G substitution at nucleotide position 2228, causing the histidine (H) at amino acid position 743 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001059908 SCV001224562 uncertain significance not provided 2023-07-25 criteria provided, single submitter clinical testing 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt SZT2 protein function. ClinVar contains an entry for this variant (Variation ID: 589156). This variant has not been reported in the literature in individuals affected with SZT2-related conditions. This variant is present in population databases (rs545593466, gnomAD 0.06%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 743 of the SZT2 protein (p.His743Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003396296 SCV004121818 uncertain significance not specified 2023-10-18 criteria provided, single submitter clinical testing Variant summary: C1orf84 c.2228A>G (p.His743Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 219442 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2228A>G in individuals affected with Early Infantile Epileptic Encephalopathy 18 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab RCV003457773 SCV004179763 uncertain significance Developmental and epileptic encephalopathy, 18 2023-04-11 criteria provided, single submitter clinical testing

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