VCV001411455.7 - ClinVar

NC_000002.11:g.(?_238233417)_(242801596_?)del

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.

(3)

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

NC_000002.11:g.(?_238233417)_(242801596_?)del

Variation ID: 1411455 Accession: VCV001411455.7

Type and length

Deletion, 4,568,180 bp

Location

Cytogenetic: 2q37.3 2: 238233417-242801596 (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	Mar 28, 2022	Nov 11, 2023	Oct 24, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_000002.11:g.(?_238233417)_(242801596_?)del

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.
HDAC4		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	535	643
KIF1A		No evidence available	No evidence available	GRCh38 GRCh37	2897	3106
AGXT		-	-	GRCh38 GRCh37	914	1034
ANKMY1		-	-	GRCh38 GRCh37	88	215
ANO7		-	-	GRCh38 GRCh37	189	346
AQP12A		-	-	GRCh38 GRCh37	24	133
AQP12B	-	-	-	GRCh38 GRCh37	47	154
ASB1		-	-	GRCh38 GRCh37	18	104
ATG4B		-	-	GRCh38 GRCh37	38	159
BOK		-	-	GRCh38 GRCh37	18	142

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.
D-2-hydroxyglutaric aciduria 1	Pathogenic (1)	criteria provided, single submitter	Oct 24, 2022	RCV003120750.4
Hereditary spastic paraplegia 30 Intellectual disability, autosomal dominant 9 Neuropathy, hereditary sensory, type 2C	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV001920651.7
not provided	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV001920650.4

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 (Oct 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	D-2-hydroxyglutaric aciduria 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003796832.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (3) PubMed: 16081310‚ 20020533‚ 21384162 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the D2HGDH gene has been identified. Loss-of-function variants in D2HGDH are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the D2HGDH gene has been identified. Loss-of-function variants in D2HGDH are known to be pathogenic (PMID: 16081310, 20020533, 21384162). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with D2HGDH-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (Dec 15, 2021)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV002186511 appears to (...more) Source: NCBI	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002186511.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (3) PubMed: 20691407‚ 24715439‚ 30848064 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the HDAC4 gene has been identified. The current clinical and genetic evidence … (more) A gross deletion of the genomic region encompassing the full coding sequence of the HDAC4 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in HDAC4 cause disease. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of HDAC4 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 20691407, 24715439, 30848064). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Pathogenic (Oct 24, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV002238305 appears to (...more) Source: NCBI	Hereditary spastic paraplegia 30 Neuropathy, hereditary sensory, type 2C Intellectual disability, autosomal dominant 9 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002238305.3 First in ClinVar: Mar 28, 2022 Last updated: Nov 11, 2023	Publications: PubMed (2) PubMed: 21820098‚ 31488895 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the KIF1A gene has been identified. Loss-of-function variants in KIF1A are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the KIF1A gene has been identified. Loss-of-function variants in KIF1A are known to be pathogenic (PMID: 21820098). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of KIF1A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 31488895). For these reasons, this variant has been classified as Pathogenic. (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the D2HGDH gene has been identified. Loss-of-function variants in D2HGDH are known to be pathogenic (PMID: 16081310, 20020533, 21384162). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with D2HGDH-related conditions. For these reasons, this variant has been classified as Pathogenic.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the HDAC4 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in HDAC4 cause disease. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of HDAC4 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 20691407, 24715439, 30848064). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the KIF1A gene has been identified. Loss-of-function variants in KIF1A are known to be pathogenic (PMID: 21820098). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of KIF1A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 31488895). For these reasons, this variant has been classified as 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

Title	Author	Journal	Year	Link
KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.	Pennings M	European journal of human genetics : EJHG	2020	PMID: 31488895
Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor.	Le TN	American journal of medical genetics. Part A	2019	PMID: 30848064
Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals.	Wheeler PG	American journal of medical genetics. Part A	2014	PMID: 24715439
KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.	Rivière JB	American journal of human genetics	2011	PMID: 21820098
Co-morbidity of Sanfilippo syndrome type C and D-2-hydroxyglutaric aciduria.	Ali Pervaiz M	Journal of neurology	2011	PMID: 21384162
Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.	Williams SR	American journal of human genetics	2010	PMID: 20691407
Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria.	Kranendijk M	Human mutation	2010	PMID: 20020533
Phenotypic heterogeneity in the presentation of D-2-hydroxyglutaric aciduria in monozygotic twins.	Misra VK	Molecular genetics and metabolism	2005	PMID: 16081310

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000002.11:g.(?_238233417)_(242801596_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...