VCV000692223.2 - ClinVar

GRCh37/hg19 5q34-35.2(chr5:166421173-173324843)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 5q34-35.2(chr5:166421173-173324843)x1

Variation ID: 692223 Accession: VCV000692223.2

Type and length

copy number loss, 6,903,911 bp

Location

Cytogenetic: 5q34-35.2 5: 166420934-173324844 (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	Oct 26, 2019	Feb 7, 2023	Sep 11, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NC_000005.9:g.(166420934_166421173)_(173324843_173324844)del

Protein change

Other names

chr5:166,421,173-173,324,843x1

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.
NKX2-5		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	625	648
FBXW11		No evidence available	Little evidence for dosage pathogenicity	GRCh38 GRCh37	83	103
TLX3		No evidence available	No evidence available	GRCh38 GRCh37	13	30
ATP6V0E1		-	-	GRCh38 GRCh37	-	26
BNIP1		-	-	GRCh38 GRCh37	20	42
BOD1		-	-	GRCh38 GRCh37	22	41
C5orf58	-	-	-	GRCh38 GRCh37	2	30
CPEB4		-	-	GRCh38 GRCh37	16	40
CREBRF		-	-	GRCh38 GRCh37	26	49
DOCK2		-	-	GRCh38 GRCh37	973	1072

There are 29 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.
Atrial septal defect 7	Pathogenic (1)	criteria provided, single submitter	Sep 11, 2019	RCV000853560.2

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 (Sep 11, 2019)	criteria provided, single submitter (ACMG CNV Guidelines, 2011) Method: clinical testing	Atrial septal defect 7 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Indiana University School of Medicine, Medical & Molecular Genetics, Indiana University School of Medicine Accession: SCV000992371.2 First in ClinVar: Oct 26, 2019 Last updated: Feb 07, 2023	Publications: PubMed (5) PubMed: 16470726‚ 17910075‚ 12868477‚ 10398271‚ 31654754 DOI: 10.1016/j.ejmg.2019.103797 DOI: 10.1016/j.ejmg.2019.103797 Comment: This is a rare deletion leading to haploinsufficiency of multiple genes. However, haploinsufficiency of NKX2.5 in this region is considered pathogenic and likely causally associated … (more) This is a rare deletion leading to haploinsufficiency of multiple genes. However, haploinsufficiency of NKX2.5 in this region is considered pathogenic and likely causally associated with cardiovascular disease in this case, including cardiac conduction disease, atrial septal defect, and mixed type left ventricular non-compaction dilated cardiomyopathy. The patient also has neurodevelopmental differences and craniofacial dysmorphism which have been variable reported in similar rare reports of copy-number losses in the 5q34-qter region. (less) Method: CMA analysis was performed on genomic DNA extracted from peripheral blood using the Applied Biosystems CytoScan HD array platform (ThermoFisher Scientific, Carlsbad, CA) consisting of 1,953,246 unique non-polymorphic copy-number probes and 743,304 single nucleotide polymorphism probes spanning the whole genome. The copy number variants (CNVs) were analyzed and reported using the NCBI human genome build 37.1 (GRCh37/hg19). Testing laboratory: Indiana University Diagnostic Genetics and Genomics (Cytogenetics Group) Testing laboratory interpretation: Pathogenic

Comment:

This is a rare deletion leading to haploinsufficiency of multiple genes. However, haploinsufficiency of NKX2.5 in this region is considered pathogenic and likely causally associated with cardiovascular disease in this case, including cardiac conduction disease, atrial septal defect, and mixed type left ventricular non-compaction dilated cardiomyopathy. The patient also has neurodevelopmental differences and craniofacial dysmorphism which have been variable reported in similar rare reports of copy-number losses in the 5q34-qter region.

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
An adult female with 5q34-q35.2 deletion: A rare syndromic presentation of left ventricular non-compaction and congenital heart disease.	Arya P	European journal of medical genetics	2020	PMID: 31654754
Chromosome 5q subtelomeric deletion syndrome.	Rauch A	American journal of medical genetics. Part C, Seminars in medical genetics	2007	PMID: 17910075
Delineation of a 2.2 Mb microdeletion at 5q35 associated with microcephaly and congenital heart disease.	Baekvad-Hansen M	American journal of medical genetics. Part A	2006	PMID: 16470726
Multicolor chromosomal bar coding characterizes a de novo interstitial deletion (5)(q33.3q35.2) in a child with multiple congenital malformations.	Schiffer C	Clinical dysmorphology	2003	PMID: 12868477
Ventricular noncompaction and distal chromosome 5q deletion.	Pauli RM	American journal of medical genetics	1999	PMID: 10398271

Text-mined citations for this variant ...

Record last updated Feb 07, 2023

ClinVar Genomic variation as it relates to human health

GRCh37/hg19 5q34-35.2(chr5:166421173-173324843)x1

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...