Submissions for variant NM_001365999.1(SZT2):c.6120_6122del (p.Val2041del)

dbSNP: rs746200792

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412881	SCV000491431	likely pathogenic	not provided	2016-02-15	criteria provided, single submitter	clinical testing	The c.5949_5951delTGT variant in the SZT2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.5949_5951delTGT variant results in an in-frame 3 base pair deletion and is predicted to cause loss of a Valine residue at position 1984 in the protein, denoted as p.Val1984del. The c.5949_5951delTGT variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Thus, the c.5949_5951delTGT variant is a strong candidate for pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735287	SCV000854440	likely pathogenic	Cryptorchidism; Global developmental delay; Seizure; Abnormality of the anterior fontanelle; Macrocephaly; Deep plantar creases; Abnormal cerebral white matter morphology; Central hypotonia		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004920	SCV001164430	likely pathogenic	Developmental and epileptic encephalopathy, 18	2022-10-06	criteria provided, single submitter	research	The heterozygous p.Val2041del variant was identified by our study in one individual with early infantile encephalopathy. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance. The p.Val1984del variant has been reported in five affected individuals (PMID: 30564332, 30755392, 35773235) but has been identified in 9/10370 (0.087%) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs756197807). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 372895) and has been interpreted as likely pathogenic by GeneDx, Children’s Hospital of Philadelphia Division of Genomic Diagnostics, and Children’s Hospital Los Angeles Center for Personalized Medicine and as a variant of uncertain significance by Invitae. Of the five affected individuals previously reported, two were homozygotes (PMID: 35773235) and two were compound heterozygotes who carried a likely pathogenic variant in trans (PMID: 30755392, PMID: 35773235), which increases the likelihood that the p.Val2041del variant is pathogenic. In vitro functional studies provide some evidence that the p.Val2041del variant may slightly impact protein function (PMID: 35773235). However, these types of assays may not accurately represent biological function. This variant is a deletion of one amino acid at position 1984 and is not predicted to alter the protein reading-frame. This deletion may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive developmental and epileptic encephalopathy 18. ACMG/AMP Criteria applied: PM3_Strong, PS3_Supporting, PM2_Supporting, PM4_Supporting (Richards 2015).
Invitae	RCV000412881	SCV001393243	pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	This variant, c.5949_5951del, results in the deletion of 1 amino acid(s) of the SZT2 protein (p.Val1984del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs746200792, gnomAD 0.09%). This variant has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 30564332, 30755392, 35773235; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372895). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SZT2 function (PMID: 30564332, 35773235). For these reasons, this variant has been classified as Pathogenic.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156093	SCV003845257	likely pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001004920	SCV004013250	likely pathogenic	Developmental and epileptic encephalopathy, 18	2023-05-31	criteria provided, single submitter	clinical testing	PS3_Supporting, PM2, PM3_Strong, PM4
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001004920	SCV004046135	likely pathogenic	Developmental and epileptic encephalopathy, 18		criteria provided, single submitter	clinical testing	This 3-base-pair in-frame deletion variant found in exon 42 of 71 leads to the loss of 1 amino acid residue but preserves the reading frame. This variant has been previously reported together with a second variant in SZT2 in individuals with global developmental delay, seizures, and hypotonia (PMID: 30755392, 30564332). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (18/282850) and is absent in the homozygous state. Based on the available evidence, c.5949_5951del (p.Val1984del) is classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000412881	SCV004123686	likely pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	SZT2: PM3:Strong, PM2, PM4:Supporting, PS3:Supporting
GenomeConnect, ClinGen	RCV001004920	SCV001423312	not provided	Developmental and epileptic encephalopathy, 18		no assertion provided	phenotyping only	Variant interpretted as Likely pathogenic and reported on 06-02-2016 by Lab or GTR ID 506013. Variant also interpretted as Likley pathogenic and reported on 08-22-2019 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.