VCV000224330.10 - ClinVar

NM_004134.7(HSPA9):c.882_883del (p.Gly295_Val296insTer)

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.

(5)

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.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004134.7(HSPA9):c.882_883del (p.Gly295_Val296insTer)

Variation ID: 224330 Accession: VCV000224330.10

Type and length

Deletion, 2 bp

Location

Cytogenetic: 5q31.2 5: 138566715-138566716 (GRCh38) [ NCBI UCSC ] 5: 137902404-137902405 (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	Jul 15, 2017	Feb 4, 2024	Aug 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004134.7:c.882_883del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004125.3:p.Gly295_Val296insTer	frameshift
NM_004134.6:c.882_883delAG
NC_000005.10:g.138566715_138566716del
NC_000005.9:g.137902404_137902405del
NG_029469.1:g.13914_13915del
LRG_1344:g.13914_13915del
LRG_1344t1:c.882_883del	LRG_1344p1:p.Gly295_Val296insTer

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000005.10:138566714:CT:

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.

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00009

The Genome Aggregation Database (gnomAD), exomes 0.00012

Exome Aggregation Consortium (ExAC) 0.00020

Links

ClinGen: CA358723 OMIM: 600548.0005 dbSNP: rs772570880 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.
HSPA9		-	-	GRCh38 GRCh37	61	80

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.
Even-plus syndrome	Pathogenic (2)	criteria provided, single submitter	Jan 1, 2016	RCV000209995.6
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jul 22, 2019	RCV001781629.4
HSPA9-related disorder	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 25, 2023	RCV003387515.2

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 (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Even-plus syndrome Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368946.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic.
Likely pathogenic (Jul 22, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002016643.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Aug 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HSPA9-related disorder Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004099075.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: PVS1, PM6_Strong, PM1
Uncertain significance (Jul 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HSPA9-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004114833.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The HSPA9 c.882_883delAG variant is predicted to result in premature protein termination (p.Val296). This variant was reported in the compound heterozygous state in an individual … (more) The HSPA9 c.882_883delAG variant is predicted to result in premature protein termination (p.Val296). This variant was reported in the compound heterozygous state in an individual with EVEN-plus syndrome (Royer-Bertrand et al. 2015. PubMed ID: 26598328) and apparently arose de novo in an individual with developmental delay (Supplementary Table 1, Deciphering Developmental Disorders Study. 2017. PubMed ID: 28135719). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-137902403-CCT-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Pathogenic (Jul 12, 2017)	no assertion criteria provided Method: literature only	EVEN-PLUS SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000265676.3 First in ClinVar: Mar 12, 2016 Last updated: Jul 15, 2017	Publications: PubMed (1) PubMed: 26598328 Comment on evidence: For discussion of the 2-bp deletion (c.882_883delAG) in the HSPA9 gene, causing a frameshift resulting in a premature termination codon (V296X), that was found in … (more) For discussion of the 2-bp deletion (c.882_883delAG) in the HSPA9 gene, causing a frameshift resulting in a premature termination codon (V296X), that was found in compound heterozygous state in a Korean girl with EVEN-plus syndrome (EVPLS; 616854) by Royer-Bertrand et al. (2015), see 600548.0004. (less)

Comment:

The HSPA9 c.882_883delAG variant is predicted to result in premature protein termination (p.Val296*). This variant was reported in the compound heterozygous state in an individual with EVEN-plus syndrome (Royer-Bertrand et al. 2015. PubMed ID: 26598328) and apparently arose de novo in an individual with developmental delay (Supplementary Table 1, Deciphering Developmental Disorders Study. 2017. PubMed ID: 28135719). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-137902403-CCT-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia.	Royer-Bertrand B	Scientific reports	2015	PMID: 26598328

Text-mined citations for rs772570880 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_004134.7(HSPA9):c.882_883del (p.Gly295_Val296insTer)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs772570880 ...