VCV001808731.1 - ClinVar

GRCh37/hg19 16p13.3(chr16:85881-1350186)x1

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 16p13.3(chr16:85881-1350186)x1

Variation ID: 1808731 Accession: VCV001808731.1

Type and length

copy number loss, -

Location

Cytogenetic: 16p13.3 16: 85881-1350186 (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	Feb 17, 2022

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.
TPSD1		Dosage sensitivity unlikely	No evidence available	GRCh38 GRCh37	40	103
SOX8		No evidence available	No evidence available	GRCh38 GRCh37	75	139
ANTKMT		-	-	GRCh38 GRCh37	26	95
ARHGDIG		-	-	GRCh38 GRCh37	22	88
AXIN1		-	-	GRCh38 GRCh37	96	168
C1QTNF8		-	-	GRCh38 GRCh37	22	84
CACNA1H		-	-	GRCh38 GRCh37	3480	3544
CAPN15		-	-	GRCh38 GRCh38 GRCh37	215	284
CCDC78		-	-	GRCh38 GRCh37	559	621
CHTF18		-	-	GRCh38 GRCh37	149	217

There are 45 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	Feb 17, 2022	RCV002474576.1

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 (Feb 17, 2022)	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: SCV002771972.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: The terminal deletion of 16p13.3 involves several protein-coding genes, including HBA1 (OMIM 141800), HBA2 (OMIM 141850), and SOX8 (OMIM 605923). Copy number losses in this … (more) The terminal deletion of 16p13.3 involves several protein-coding genes, including HBA1 (OMIM 141800), HBA2 (OMIM 141850), and SOX8 (OMIM 605923). Copy number losses in this region are associated with autosomal dominant chromosome 16-related alpha-thalassemia/intellectual disability syndrome (ATR-16; OMIM 141750), which is characterized by a variable phenotype which can include mild to moderate intellectual disability (ID), developmental disorders (DD), nonspecific dysmorphic features, alpha-thalassemia (OMIM 604131), and hemoglobin H disease (HBH; OMIM 613978). While SOX8 has been proposed as the critical element for ID in ATR-16 (Pheifer 2000), there are conflicting reports demonstrating that SOX8 involvement is neither necessary nor sufficient to cause ID (Bezerra 2008, Gibbons 2012). Additionally, heterozygous sequence variants of HBA1 and HBA2 are associated with autosomal dominant Heinz body anemias (OMIM 140700) and autosomal dominant familial erythrocytosis-7 (ECYT7; OMIM 617981), while heterozygous sequence variants of NPRL3 (OMIM 600928), STUB1 (OMIM 607207), and CACNA1H (OMIM 607904) are associated with autosomal dominant familial focal epilepsy with variable foci (FFEVF; OMIM 617118), spinocerebellarataxia-48 (SCA48; OMIM 618093), and familial hyperaldosteronism type IV (HALD4; OMIM 617027) respectively. As hemizygous deletions of this interval have been associated with a clinical phenotype, and there are no similar copy number losses of this region in the general populations of the Database of Genomic Variants, the classification of this copy number variant (CNV) is pathogenic. (less)

Comment:

The terminal deletion of 16p13.3 involves several protein-coding genes, including HBA1 (OMIM 141800), HBA2 (OMIM 141850), and SOX8 (OMIM 605923). Copy number losses in this region are associated with autosomal dominant chromosome 16-related alpha-thalassemia/intellectual disability syndrome (ATR-16; OMIM 141750), which is characterized by a variable phenotype which can include mild to moderate intellectual disability (ID), developmental disorders (DD), nonspecific dysmorphic features, alpha-thalassemia (OMIM 604131), and hemoglobin H disease (HBH; OMIM 613978). While SOX8 has been proposed as the critical element for ID in ATR-16 (Pheifer 2000), there are conflicting reports demonstrating that SOX8 involvement is neither necessary nor sufficient to cause ID (Bezerra 2008, Gibbons 2012). Additionally, heterozygous sequence variants of HBA1 and HBA2 are associated with autosomal dominant Heinz body anemias (OMIM 140700) and autosomal dominant familial erythrocytosis-7 (ECYT7; OMIM 617981), while heterozygous sequence variants of NPRL3 (OMIM 600928), STUB1 (OMIM 607207), and CACNA1H (OMIM 607904) are associated with autosomal dominant familial focal epilepsy with variable foci (FFEVF; OMIM 617118), spinocerebellarataxia-48 (SCA48; OMIM 618093), and familial hyperaldosteronism type IV (HALD4; OMIM 617027) respectively. As hemizygous deletions of this interval have been associated with a clinical phenotype, and there are no similar copy number losses of this region in the general populations of the Database of Genomic Variants, the classification of this copy number variant (CNV) is pathogenic.

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 16p13.3(chr16:85881-1350186)x1

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...