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NM_001172509.2(SATB2):c.1166G>A (p.Arg389His) AND Chromosome 2q32-q33 deletion syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Sep 19, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002471277.3

Allele description

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

Gene:
SATB2:SATB homeobox 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q33.1
Genomic location:
Preferred name:
NM_001172509.2(SATB2):c.1166G>A (p.Arg389His)
HGVS:
  • NC_000002.12:g.199348708C>T
  • NG_016976.2:g.127559G>A
  • NM_001172509.2:c.1166G>AMANE SELECT
  • NM_001172517.1:c.1166G>A
  • NM_015265.4:c.1166G>A
  • NP_001165980.1:p.Arg389His
  • NP_001165988.1:p.Arg389His
  • NP_056080.1:p.Arg389His
  • NC_000002.11:g.200213431C>T
  • NM_001172509.1:c.1166G>A
  • NM_015265.3:c.1166G>A
Protein change:
R389H
Molecular consequence:
  • NM_001172509.2:c.1166G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001172517.1:c.1166G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015265.4:c.1166G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Chromosome 2q32-q33 deletion syndrome (GLASS)
Synonyms:
Glass syndrome; 2q33.1 deletion syndrome
Identifiers:
MONDO: MONDO:0012864; MedGen: C2676739; Orphanet: 251019; OMIM: 612313

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002769121Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Feb 2, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003298914Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Sep 19, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Mutation update for the SATB2 gene.

Zarate YA, Bosanko KA, Caffrey AR, Bernstein JA, Martin DM, Williams MS, Berry-Kravis EM, Mark PR, Manning MA, Bhambhani V, Vargas M, Seeley AH, Estrada-Veras JI, van Dooren MF, Schwab M, Vanderver A, Melis D, Alsadah A, Sadler L, Van Esch H, Callewaert B, Oostra A, et al.

Hum Mutat. 2019 Aug;40(8):1013-1029. doi: 10.1002/humu.23771. Epub 2019 Jun 18. Review.

PubMed [citation]
PMID:
31021519
PMCID:
PMC11431158

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (6)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769121.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

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

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

From Invitae, SCV003298914.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

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).

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

Last Updated: May 1, 2024