VCV001723662.9 - ClinVar

NM_001172509.2(SATB2):c.1166G>A (p.Arg389His)

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.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(2); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001172509.2(SATB2):c.1166G>A (p.Arg389His)

Variation ID: 1723662 Accession: VCV001723662.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q33.1 2: 199348708 (GRCh38) [ NCBI UCSC ] 2: 200213431 (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	Nov 19, 2022	Jul 23, 2024	Nov 11, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001172509.2:c.1166G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001165980.1:p.Arg389His	missense
NM_001172517.1:c.1166G>A	NP_001165988.1:p.Arg389His	missense
NM_015265.4:c.1166G>A	NP_056080.1:p.Arg389His	missense
NC_000002.12:g.199348708C>T
NC_000002.11:g.200213431C>T
NG_016976.2:g.127559G>A

... more HGVS ... less HGVS

Protein change

R389H

Other names

Canonical SPDI

NC_000002.12:199348707: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

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.
SATB2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	639	817

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 11, 2022	RCV002308936.2
Chromosome 2q32-q33 deletion syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 19, 2022	RCV002471277.5
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jun 30, 2021	RCV003099134.2
See cases	Uncertain significance (1)	criteria provided, single submitter	Sep 30, 2022	RCV003128454.1
Neurodevelopmental disorder	Likely pathogenic (1)	criteria provided, single submitter	Sep 5, 2022	RCV003389081.1

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.
Uncertain significance (Sep 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV003804821.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG categories: PM2,PP3 Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) Age: 0-9 years Sex: male Tissue: blood
Pathogenic (Nov 11, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002601233.2 First in ClinVar: Nov 19, 2022 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33004838, 34660482, 31302918) (less)
Likely pathogenic (Sep 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV004101235.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023
Likely pathogenic (Sep 19, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Chromosome 2q32-q33 deletion syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003298914.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 24884844‚ 28151491‚ 31302918 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg389 amino acid residue in SATB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24884844, 28151491; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 SATB2 protein function. This missense change has been observed in individual(s) with Glass syndrome (PMID: 31302918). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the SATB2 protein (p.Arg389His). (less)
Uncertain significance (Jun 30, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003561046.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.1166G>A (p.R389H) alteration is located in exon 8 (coding exon 6) of the SATB2 gene. This alteration results from a G to A substitution … (more) The c.1166G>A (p.R389H) alteration is located in exon 8 (coding exon 6) of the SATB2 gene. This alteration results from a G to A substitution at nucleotide position 1166, causing the arginine (R) at amino acid position 389 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Chromosome 2q32-q33 deletion syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769121.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 28151491‚ 31021519‚ 31302918 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Glass syndrome (MIM#612313). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. The variant is located in the center region of CUT1 domain where previously reported pathogenic variants clustered (PMID: 28151491, DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg389Cys) and p.(Arg389Leu) have been reported in many individuals with SATB2-related neurodevelopmental disorder (PMIDs: 31021519, 28151491, ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as de novo in two individuals with global developmental delay or Glass syndrome (DECIPHER, PMID: 31302918). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33004838, 34660482, 31302918)

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg389 amino acid residue in SATB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24884844, 28151491; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 SATB2 protein function. This missense change has been observed in individual(s) with Glass syndrome (PMID: 31302918). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the SATB2 protein (p.Arg389His).

Comment:

The c.1166G>A (p.R389H) alteration is located in exon 8 (coding exon 6) of the SATB2 gene. This alteration results from a G to A substitution at nucleotide position 1166, causing the arginine (R) at amino acid position 389 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Glass syndrome (MIM#612313). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. The variant is located in the center region of CUT1 domain where previously reported pathogenic variants clustered (PMID: 28151491, DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg389Cys) and p.(Arg389Leu) have been reported in many individuals with SATB2-related neurodevelopmental disorder (PMIDs: 31021519, 28151491, ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as de novo in two individuals with global developmental delay or Glass syndrome (DECIPHER, PMID: 31302918). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
[Analysis of SATB2 gene mutation in a child with Glass syndrome].	Lin M	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2019	PMID: 31302918
Mutation update for the SATB2 gene.	Zarate YA	Human mutation	2019	PMID: 31021519
Clinical and molecular consequences of disease-associated de novo mutations in SATB2.	Bengani H	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28151491
PhenoVar: a phenotype-driven approach in clinical genomics for the diagnosis of polymalformative syndromes.	Trakadis YJ	BMC medical genomics	2014	PMID: 24884844

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001172509.2(SATB2):c.1166G>A (p.Arg389His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...