ClinVar Genomic variation as it relates to human health

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

A heterozygous missense variant was identified, NM_015284.3(SZT2):c.9695G>T in exon 68 of 71 of the SZT2 gene. This substitution is predicted to create a major amino acid change from a glycine to a valine at position 3232 of the protein, NP_056099.3(SZT2):p.(Gly3232Val). The glycine at this position has moderate conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0069% (14 heterozygotes, 0 homozygotes). The variant has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3232 of the SZT2 protein (p.Gly3232Val). This variant is present in population databases (rs371736872, gnomAD 0.01%). 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: 955816). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

The c.9695G>T (p.G3232V) alteration is located in exon 68 (coding exon 68) of the SZT2 gene. This alteration results from a G to T substitution at nucleotide position 9695, causing the glycine (G) at amino acid position 3232 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

SZT2: PM2

Variant interpreted as Uncertain significance and reported on 09-08-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.