NM_001365999.1:c.6120_6122delTGT

Variant names:

• chr1-43437253-CGTT-C
• rs746200792
• NM_001365999.1:c.6120_6122delTGT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM4_Supporting PP5_Very_Strong

The NM_001365999.1(SZT2):​c.6120_6122delTGT​(p.Val2041del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: SZT2 NM_001365999.1 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

SZT2 (HGNC:29040): (SZT2 subunit of KICSTOR complex) The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis. [provided by RefSeq, Jun 2011]

SZT2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001365999.1. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-43437253-CGTT-C is Pathogenic according to our data. Variant chr1-43437253-CGTT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365999.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	NM_001365999.1	MANE Select	c.6120_6122delTGT	p.Val2041del	disruptive_inframe_deletion	Exon 43 of 72	NP_001352928.1
	SZT2	NM_015284.4		c.5949_5951delTGT	p.Val1984del	disruptive_inframe_deletion	Exon 42 of 71	NP_056099.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.6120_6122delTGT	p.Val2041del	disruptive_inframe_deletion	Exon 43 of 72	ENSP00000489255.1
	SZT2	ENST00000562955.2	TSL:5	c.5949_5951delTGT	p.Val1984del	disruptive_inframe_deletion	Exon 42 of 71	ENSP00000457168.1
	SZT2	ENST00000639197.1	TSL:6	n.1549_1551delTGT		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000636 AC: 16 AN: 251458 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461894 Hom.: 0 AF XY: 0.0000550 AC XY: 40 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112012

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 15, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SZT2: PM3:Strong, PM2, PM4:Supporting, PS3:Supporting

Mar 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Developmental and epileptic encephalopathy, 18 Pathogenic:3 Other:1

Oct 06, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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).

May 31, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Supporting, PM2, PM3_Strong, PM4

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: 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.

SZT2-related disorder Pathogenic:1

May 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SZT2 c.5949_5951delTGT variant is predicted to result in an in-frame deletion (p.Val1984del). This variant has been reported in the compound heterozygous state and homozygous state in at least four individuals with epileptic encephalopathy (Uittenbogaard et al. 2018. PubMed ID: 30564332; Calhoun et al. 2022. PubMed ID: 35773235). In vitro studies suggest that this variant alters protein function (Uittenbogaard et al. 2018. PubMed ID: 30564332). This variant is reported in 0.087% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=63/37	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746200792; hg19: chr1-43902924;