VCV001807801.1 - ClinVar

GRCh37/hg19 Xq27.1-27.3(chrX:139510129-145119351)x3

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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

GRCh37/hg19 Xq27.1-27.3(chrX:139510129-145119351)x3

Variation ID: 1807801 Accession: VCV001807801.1

Type and length

copy number gain, -

Location

Cytogenetic: Xq27.1-27.3 X: 139510129-145119351 (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	Dec 31, 2022	Dec 31, 2022	Nov 10, 2021

HGVS

Protein change

Other names

Canonical SPDI

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.
SOX3		No evidence available	Little evidence for dosage pathogenicity	GRCh38 GRCh37	84	294
CDR1		-	-	GRCh38 GRCh37	-	202
LDOC1		-	-	GRCh38 GRCh37	4	203
MAGEC1		-	-	GRCh38 GRCh37	151	344
MAGEC2		-	-	GRCh38 GRCh37	24	214
MAGEC3		-	-	GRCh38 GRCh37	60	254
SLITRK2		-	-	GRCh38 GRCh37	55	249
SLITRK4		-	-	GRCh38 GRCh37	30	222
SPANXA1		-	-	GRCh38 GRCh37	-	198
SPANXA2		-	-	GRCh38 GRCh37	-	198

There are 8 more genes affected by this variant. See the full set of genes in Variation Viewer (GRCh37) and ClinGen Dosage Sensitivity Map.

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 10, 2021	RCV002472607.1

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.
Pathogenic (Nov 10, 2021)	criteria provided, single submitter (ACMG/ClinGen CNV Guidelines, 2019) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002772475.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: The copy number gain of Xq27.1q27.3 involves several protein-coding genes, including a full copy of SOX3 (OMIM 313430), and is expected to cause developmental and/or … (more) The copy number gain of Xq27.1q27.3 involves several protein-coding genes, including a full copy of SOX3 (OMIM 313430), and is expected to cause developmental and/or behavioral abnormalities. In males, triplosensitivity of SOX3 are implicated in X-linked intellectual disability with isolated growth hormone deficiency (OMIM 300123) or X-linked panhypopituitarism (OMIM 312000) (Rosolowsky 2020, Arya 2019, Stagi 2014, Bauters 2014, Woods 2005, Solomon 2004). Additionally, duplications of SOX3 have been reported in neural tube defects (Hureaux 2019, Uguen 2015, Bauters 2014) or male 46, XX sex reversal with or without other congenital anomalies (Chaves 2019, Nagamani 2012, Sutton 2011, Lachlan 2004). One of the reported patients with 46,XX sex reversal had a somewhat similar 6-Mb duplication and presented with a complex phenotype also including scrotal hypoplasia, microcephaly, developmental delay, and growth retardation (Sutton 2011). Further, interstitial duplications partially overlapping this region are associated with Xq27.3-q28 duplication syndrome (OMIM 300869), an X-linked neurodevelopmental disorder characterized by intellectual disability, delayed psychomotor development, facial dysmorphism, short stature, small hands and feet, and primary hypogonadism. Female carriers may have short stature and premature ovarian failure depending on X-inactivation patterns (Chaves 2019, Rio 2010, Lachlan 2004). However, the critical gene for Xq27.3-q28 duplication syndrome, FMR1 (OMIM 309550), is not encompassed in the current interval. Currently, the clinical significance of this copy number variant (CNV) is interpreted as pathogenic. Of note, clinical presentation of this finding in a female is typically dependent upon X-inactivation status. References: Arya et al., Horm Res Paediatr. 2019;92(6):382-389. PMID: 31678974. Bauters et al., Am J Med Genet A. 2014 Aug;164A(8):1947-52. PMID: 24737742. Chaves et al., Sci Rep. 2019 Nov 28;9(1):17776. PMID: 31780800. Hureaux et al. Prenat Diagn. 2019 Oct;39(11):1026-1034. PMID: 31299102. Lachlan et al., Hum Genet. 2004 Oct;115(5):399-408. PMID: 15338277. Nagamani et al., Neurogenetics. 2012 Nov;13(4):333-9. PMID: 22890812. Rosolowsky et al., J Pediatr Endocrinol Metab. 2020 Mar 26;33(3):443-447. PMID: 26352083. Solomon et al., J Med Genet. 2004 Sep;41(9):669-78. PMID: 15342697. Stagi et al., Hormones (Athens). 2014 Oct-Dec;13(4):552-60. PMID: 25402377. Sutton et al., J Clin Invest. 2011 Jan;121(1):328-41. PMID: 21183788. Uguen et al., Am J Med Genet A. 2015 Jul;167(7):1676-8. PMID: 25900196. Woods et al., Am J Hum Genet. 2005 May;76(5):833-49. PMID: 15800844. (less)

Comment:

The copy number gain of Xq27.1q27.3 involves several protein-coding genes, including a full copy of SOX3 (OMIM 313430), and is expected to cause developmental and/or behavioral abnormalities. In males, triplosensitivity of SOX3 are implicated in X-linked intellectual disability with isolated growth hormone deficiency (OMIM 300123) or X-linked panhypopituitarism (OMIM 312000) (Rosolowsky 2020, Arya 2019, Stagi 2014, Bauters 2014, Woods 2005, Solomon 2004). Additionally, duplications of SOX3 have been reported in neural tube defects (Hureaux 2019, Uguen 2015, Bauters 2014) or male 46, XX sex reversal with or without other congenital anomalies (Chaves 2019, Nagamani 2012, Sutton 2011, Lachlan 2004). One of the reported patients with 46,XX sex reversal had a somewhat similar 6-Mb duplication and presented with a complex phenotype also including scrotal hypoplasia, microcephaly, developmental delay, and growth retardation (Sutton 2011). Further, interstitial duplications partially overlapping this region are associated with Xq27.3-q28 duplication syndrome (OMIM 300869), an X-linked neurodevelopmental disorder characterized by intellectual disability, delayed psychomotor development, facial dysmorphism, short stature, small hands and feet, and primary hypogonadism. Female carriers may have short stature and premature ovarian failure depending on X-inactivation patterns (Chaves 2019, Rio 2010, Lachlan 2004). However, the critical gene for Xq27.3-q28 duplication syndrome, FMR1 (OMIM 309550), is not encompassed in the current interval. Currently, the clinical significance of this copy number variant (CNV) is interpreted as pathogenic. Of note, clinical presentation of this finding in a female is typically dependent upon X-inactivation status. References: Arya et al., Horm Res Paediatr. 2019;92(6):382-389. PMID: 31678974. Bauters et al., Am J Med Genet A. 2014 Aug;164A(8):1947-52. PMID: 24737742. Chaves et al., Sci Rep. 2019 Nov 28;9(1):17776. PMID: 31780800. Hureaux et al. Prenat Diagn. 2019 Oct;39(11):1026-1034. PMID: 31299102. Lachlan et al., Hum Genet. 2004 Oct;115(5):399-408. PMID: 15338277. Nagamani et al., Neurogenetics. 2012 Nov;13(4):333-9. PMID: 22890812. Rosolowsky et al., J Pediatr Endocrinol Metab. 2020 Mar 26;33(3):443-447. PMID: 26352083. Solomon et al., J Med Genet. 2004 Sep;41(9):669-78. PMID: 15342697. Stagi et al., Hormones (Athens). 2014 Oct-Dec;13(4):552-60. PMID: 25402377. Sutton et al., J Clin Invest. 2011 Jan;121(1):328-41. PMID: 21183788. Uguen et al., Am J Med Genet A. 2015 Jul;167(7):1676-8. PMID: 25900196. Woods et al., Am J Hum Genet. 2005 May;76(5):833-49. PMID: 15800844.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Dec 31, 2022

ClinVar Genomic variation as it relates to human health

GRCh37/hg19 Xq27.1-27.3(chrX:139510129-145119351)x3

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...