VCV001808266.1 - ClinVar

GRCh37/hg19 22q13.31-13.33(chr22:44390702-51137629)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 22q13.31-13.33(chr22:44390702-51137629)x1

Variation ID: 1808266 Accession: VCV001808266.1

Type and length

copy number loss, -

Location

Cytogenetic: 22q13.31-13.33 22: 44390702-51137629 (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	Jun 1, 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.
SHANK3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	871	1101
ADM2		-	-	GRCh38 GRCh37	18	172
ALG12		-	-	GRCh38 GRCh37	528	766
ARHGAP8		-	-	GRCh38 GRCh37	-	165
ARSA		-	-	GRCh38 GRCh37	1256	1424
ATXN10		-	-	GRCh38 GRCh37	37	125
BRD1		-	-	GRCh38 GRCh37	84	225
CDPF1	-	-	-	GRCh38 GRCh37	9	95
CELSR1		-	-	GRCh38 GRCh37	512	662
CERK		-	-	GRCh38 GRCh37	47	154

There are 56 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	Jun 1, 2022	RCV002473583.1

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 (Jun 01, 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: SCV002773300.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: The copy number loss of 22q13.2q13.33 involves multiple coding genes, including several exons from the 5' portion of SHANK3 (OMIM 606230). Haploinsufficiency of SHANK3 is … (more) The copy number loss of 22q13.2q13.33 involves multiple coding genes, including several exons from the 5' portion of SHANK3 (OMIM 606230). Haploinsufficiency of SHANK3 is associated with Phelan-McDermid syndrome (PHMDS; OMIM 606232). The clinical features of the syndromeare variable, and include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior, seizures, and minor dysmorphic features. There may be a genotype-phenotype correlation with respect to thesize of the deleted segment, however, the correlation is not 100%, as the clinical features in individuals with the same size deletion may vary significantly. The loss of 22q13.3 can result from simple deletion, unbalanced translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome22 (Phelan 2008; Sarasua 2014; Zwanenburg 2016; Phelan 2001). Although SHANK3 is the primary phenotype gene for the neurologicalfeatures of the syndrome, haploinsufficiency of other genes likely contributes to the phenotype, as well. (Disciglio 2014).References:Disciglio et al. Am J Med Genet A. 2014;164A(7):1666-76. PMID:24700646.Phelan. Orphanet J Rare Dis. 2008;3:14. PMID: 18505557.Phelan et al. Am J Med Genet. 2001;101(2):91-9. PMID: 11391650. Phelan K and McDermid HE. The 22q13.3 Deletion Syndrome(Phelan-McDermid Syndrome). Mol Syndromol. 2012;2(3-5):186-201.PMID:?22670140 .Phelan K, Rogers RC, Boccuto L. Phelan-McDermid Syndrome. 2005 May 11[Updated 2018 Jun 7]. In GeneReviews (available from:https://www.ncbi.nlm.nih.gov/books/NBK1198 ). Sarasua et al. Hum Genet. 2014;133(7):847-59. PMID: 24481935.Ziats et al. Eur J Med Genet. 2020;63(11):104042. PMID: 32822873.Zwanenburg et al. J Neurodev Disord. 2016;8:16. PMID: 27118998. (less)

Comment:

The copy number loss of 22q13.2q13.33 involves multiple coding genes, including several exons from the 5' portion of SHANK3 (OMIM 606230). Haploinsufficiency of SHANK3 is associated with Phelan-McDermid syndrome (PHMDS; OMIM 606232). The clinical features of the syndromeare variable, and include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior, seizures, and minor dysmorphic features. There may be a genotype-phenotype correlation with respect to thesize of the deleted segment, however, the correlation is not 100%, as the clinical features in individuals with the same size deletion may vary significantly. The loss of 22q13.3 can result from simple deletion, unbalanced translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome22 (Phelan 2008; Sarasua 2014; Zwanenburg 2016; Phelan 2001). Although SHANK3 is the primary phenotype gene for the neurologicalfeatures of the syndrome, haploinsufficiency of other genes likely contributes to the phenotype, as well. (Disciglio 2014).References:Disciglio et al. Am J Med Genet A. 2014;164A(7):1666-76. PMID:24700646.Phelan. Orphanet J Rare Dis. 2008;3:14. PMID: 18505557.Phelan et al. Am J Med Genet. 2001;101(2):91-9. PMID: 11391650. Phelan K and McDermid HE. The 22q13.3 Deletion Syndrome(Phelan-McDermid Syndrome). Mol Syndromol. 2012;2(3-5):186-201.PMID:?22670140 .Phelan K, Rogers RC, Boccuto L. Phelan-McDermid Syndrome. 2005 May 11[Updated 2018 Jun 7]. In GeneReviews (available from:https://www.ncbi.nlm.nih.gov/books/NBK1198 ). Sarasua et al. Hum Genet. 2014;133(7):847-59. PMID: 24481935.Ziats et al. Eur J Med Genet. 2020;63(11):104042. PMID: 32822873.Zwanenburg et al. J Neurodev Disord. 2016;8:16. PMID: 27118998.

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 Mar 26, 2023

ClinVar Genomic variation as it relates to human health

GRCh37/hg19 22q13.31-13.33(chr22:44390702-51137629)x1

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...