NM_001365999.1(SZT2):c.6120_6122del (p.Val2041del) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Feb 18, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_001365999.1(SZT2):c.6120_6122del (p.Val2041del)]

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

SZT2:SZT2 subunit of KICSTOR complex [Gene - OMIM - HGNC]
Variant type:
Cytogenetic location:
Genomic location:
Preferred name:
NM_001365999.1(SZT2):c.6120_6122del (p.Val2041del)
  • NC_000001.11:g.43437256_43437258del
  • NG_029091.1:g.52372_52374del
  • NM_001365999.1:c.6120_6122delMANE SELECT
  • NM_015284.4:c.5949_5951del
  • NP_001352928.1:p.Val2041del
  • NP_056099.3:p.Val1984del
  • NC_000001.10:g.43902925_43902927del
  • NC_000001.10:g.43902927_43902929del
  • NM_015284.3:c.5949_5951del
  • NM_015284.3:c.5949_5951delTGT
  • p.Val1984del
Protein change:
dbSNP: rs746200792
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001365999.1:c.6120_6122del - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_015284.4:c.5949_5951del - inframe_deletion - [Sequence Ontology: SO:0001822]


MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000491431GeneDxcriteria provided, single submitter
Likely pathogenic
(Feb 15, 2016)
germlineclinical testing

Citation Link,

SCV001393243Invitaecriteria provided, single submitter
Uncertain significance
(Feb 18, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Novel metabolic signatures of compound heterozygous Szt2 variants in a case of early-onset of epileptic encephalopathy.

Uittenbogaard M, Gropman A, Brantner CA, Chiaramello A.

Clin Case Rep. 2018 Dec;6(12):2376-2384. doi: 10.1002/ccr3.1868.

PubMed [citation]

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From GeneDx, SCV000491431.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001393243.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)


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, ExAC 0.007%). This variant has been observed in an individual affected with early-onset epileptic encephalopathy (PMID: 30564332). ClinVar contains an entry for this variant (Variation ID: 372895). This variant has been reported to reduce mitochondrial activity and alter mitochondrial morphology in combination with a second SZT2 variant in patient fibroblasts (PMID: 30564332). 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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 12, 2021

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