VCV000583607.12 - ClinVar

NC_000009.12:g.(?_128632127)_(128640939_?)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.

(2)

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_000009.12:g.(?_128632127)_(128640939_?)del

Variation ID: 583607 Accession: VCV000583607.12

Type and length

Deletion, 8,813 bp

Location

Cytogenetic: 9q34.11 9: 128632127-128640939 (GRCh38) [ NCBI UCSC ] 9: 131394406-131403218 (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 10, 2018	Jun 9, 2024	Aug 8, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_000009.12:g.(?_128632127)_(128640939_?)del
NC_000009.11:g.(?_131394406)_(131403218_?)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.
DYNC2I2		-	-	GRCh38 GRCh37	347	545
LOC126860772	-	-	-	GRCh38	-	163
SPTAN1		-	-	GRCh38 GRCh37	2660	2719

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.
Short-rib thoracic dysplasia 11 with or without polydactyly	Pathogenic (1)	criteria provided, single submitter	Aug 8, 2022	RCV000707899.11
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Aug 8, 2022	RCV001345332.10

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 (Aug 08, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Early infantile epileptic encephalopathy with suppression bursts Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001539439.5 First in ClinVar: Mar 22, 2021 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 33578420 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SPTAN1 protein in which other variant(s) (p.Arg2261) have … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SPTAN1 protein in which other variant(s) (p.Arg2261) have been determined to be pathogenic (PMID: 33578420). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with SPTAN1-related conditions. This variant is a gross deletion of the genomic region encompassing exon(s) 53-57 of the SPTAN1 gene, which includes the termination codon. This deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. While this deletion is not anticipated to lead to nonsense mediated decay, it is expected to alter mRNA translation or result in a truncated protein product. (less)
Pathogenic (Aug 08, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Short-rib thoracic dysplasia 11 with or without polydactyly Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000837009.6 First in ClinVar: Oct 10, 2018 Last updated: Jun 09, 2024	Publications: PubMed (4) PubMed: 28492532‚ 24183449‚ 24183451‚ 28379358 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the WDR34 gene has been identified. Loss-of-function variants in WDR34 are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the WDR34 gene has been identified. Loss-of-function variants in WDR34 are known to be pathogenic (PMID: 24183449, 24183451, 28379358). 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 WDR34-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SPTAN1 protein in which other variant(s) (p.Arg2261*) have been determined to be pathogenic (PMID: 33578420). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with SPTAN1-related conditions. This variant is a gross deletion of the genomic region encompassing exon(s) 53-57 of the SPTAN1 gene, which includes the termination codon. This deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. While this deletion is not anticipated to lead to nonsense mediated decay, it is expected to alter mRNA translation or result in a truncated protein product.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the WDR34 gene has been identified. Loss-of-function variants in WDR34 are known to be pathogenic (PMID: 24183449, 24183451, 28379358). 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 WDR34-related conditions. 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
A novel de novo SPTAN1 nonsense variant causes hereditary motor neuropathy in a Chinese family.	Dong HL	Brain : a journal of neurology	2021	PMID: 33578420
Loss of dynein-2 intermediate chain Wdr34 results in defects in retrograde ciliary protein trafficking and Hedgehog signaling in the mouse.	Wu C	Human molecular genetics	2017	PMID: 28379358
Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy.	Schmidts M	American journal of human genetics	2013	PMID: 24183451
WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia.	Huber C	American journal of human genetics	2013	PMID: 24183449

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000009.12:g.(?_128632127)_(128640939_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...