VCV001043590.27 - ClinVar

NM_002971.6(SATB1):c.1588G>A (p.Glu530Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002971.6(SATB1):c.1588G>A (p.Glu530Lys)

Variation ID: 1043590 Accession: VCV001043590.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.3 3: 18352183 (GRCh38) [ NCBI UCSC ] 3: 18393675 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 22, 2021	Oct 20, 2024	Jul 31, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002971.6:c.1588G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002962.1:p.Glu530Lys	missense
NM_001131010.4:c.1588G>A	NP_001124482.1:p.Glu530Lys	missense
NM_001195470.3:c.1588G>A	NP_001182399.1:p.Glu530Lys	missense
NM_001322871.2:c.1588G>A	NP_001309800.1:p.Glu530Lys	missense
NM_001322872.2:c.1588G>A	NP_001309801.1:p.Glu530Lys	missense
NM_001322873.2:c.1588G>A	NP_001309802.1:p.Glu530Lys	missense
NM_001322874.2:c.1588G>A	NP_001309803.1:p.Glu530Lys	missense
NM_001322875.2:c.1588G>A	NP_001309804.1:p.Glu530Lys	missense
NM_001322876.2:c.1372G>A	NP_001309805.1:p.Glu458Lys	missense
NC_000003.12:g.18352183C>T
NC_000003.11:g.18393675C>T
NG_027814.2:g.98406G>A

... more HGVS ... less HGVS

Protein change

E530K, E458K

Other names

Canonical SPDI

NC_000003.12:18352182:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 602075.0006 dbSNP: rs1694399198 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SATB1		-	-	GRCh38 GRCh37	140	165

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Kohlschutter-Tonz syndrome-like	Pathogenic (2)	criteria provided, single submitter	Jan 3, 2022	RCV001347719.7
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 31, 2023	RCV001780262.22

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Kohlschutter-Tonz syndrome-like Affected status: yes Allele origin: germline	3billion Accession: SCV002058576.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:33513338 PMID:33513338 Comment: The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 33513338, PS4_S). The variant has been previously reported as de novo in a … (more) The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 33513338, PS4_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 33513338, PS2_S).Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 33513338, , PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.985, PP3_P). A missense variant is a common mechanism associated with Kohlschutter-Tonz syndrome-like (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Bulbar palsy (present) , Seizure (present) , Global developmental delay (present) , Spastic tetraparesis (present)
Pathogenic (Aug 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026026.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PS1, PM1, PM2_SUP, PS3
Likely pathogenic (Jul 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019122.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Apr 30, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002198850.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 33513338 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects SATB1 protein function (PMID: 33513338). This variant … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects SATB1 protein function (PMID: 33513338). This variant has been observed in individual(s) with clinical features of SATB1-related conditions (PMID: 33513338). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 530 of the SATB1 protein (p.Glu530Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. (less)
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003916413.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: SATB1: PS2, PM2, PS4:Moderate, PP2, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Jul 05, 2023)	no assertion criteria provided Method: literature only	DEN HOED-DE BOER-VOISIN SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV001541993.3 First in ClinVar: Mar 22, 2021 Last updated: Jul 08, 2023	Publications: PubMed (1) PubMed: 33513338 Comment on evidence: In 8 unrelated patients (patients 30-37) with den Hoed-de Boer-Voisin syndrome (DHDBV; 619229), den Hoed et al. (2021) identified a de novo heterozygous c.1588G-A transition … (more) In 8 unrelated patients (patients 30-37) with den Hoed-de Boer-Voisin syndrome (DHDBV; 619229), den Hoed et al. (2021) identified a de novo heterozygous c.1588G-A transition (c.1588G-A, NM_001131010.4) in the SATB1 gene, resulting in a glu530-to-lys (E530K) substitution at a conserved residue in the CUT2 domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the mutant protein displayed a cage-like clustered nuclear pattern, strongly colocalizing with DNA and causing increased transcriptional repression of the IL2 promoter, consistent with stronger binding of the mutant SATB1 transcription factor to its target. (less)

Comment:

The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 33513338, PS4_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 33513338, PS2_S).Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 33513338, , PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.985, PP3_P). A missense variant is a common mechanism associated with Kohlschutter-Tonz syndrome-like (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects SATB1 protein function (PMID: 33513338). This variant has been observed in individual(s) with clinical features of SATB1-related conditions (PMID: 33513338). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 530 of the SATB1 protein (p.Glu530Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.	den Hoed J	American journal of human genetics	2021	PMID: 33513338

Text-mined citations for rs1694399198 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_002971.6(SATB1):c.1588G>A (p.Glu530Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1694399198 ...