VCV002499136.15 - ClinVar

NM_001127898.4(CLCN5):c.1773TGT[1] (p.Val593del)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001127898.4(CLCN5):c.1773TGT[1] (p.Val593del)

Variation ID: 2499136 Accession: VCV002499136.15

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: Xp11.23 X: 50090143-50090145 (GRCh38) [ NCBI UCSC ] X: 49854800-49854802 (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	Apr 23, 2023	Oct 20, 2024	May 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001127898.4:c.1773TGT[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121370.1:p.Val593del	inframe deletion
NM_000084.5:c.1563TGT[1]	NP_000075.1:p.Val523del	inframe deletion
NM_001127899.4:c.1773TGT[1]	NP_001121371.1:p.Val593del	inframe deletion
NM_001282163.2:c.1623TGT[1]	NP_001269092.1:p.Val543del	inframe deletion
NR_073607.1:n.1854_1856TGT[1]
NC_000023.11:g.50090144TGT[1]
NC_000023.10:g.49854801TGT[1]
NG_007159.3:g.172529TGT[1]
NG_087754.1:g.405TGT[1]

... more HGVS ... less HGVS

Protein change

V523del, V543del, V593del

Other names

Canonical SPDI

NC_000023.11:50090142:TTGTTGT:TTGT

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.
CLCN5		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	339	606
LOC126863258	-	-	-	GRCh38	-	178

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 (2)	criteria provided, multiple submitters, no conflicts	May 1, 2023	RCV003221437.15

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 (Mar 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004299560.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 19546591‚ 33987651‚ 24081861‚ 25907713‚ 31328266 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects CLCN5 function (PMID: 19546591, 33987651). Algorithms developed … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects CLCN5 function (PMID: 19546591, 33987651). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant is also known as 523delVal, p.V592_V593delinsV, or p.Val522del. This variant has been observed in individuals with Dent disease (PMID: 19546591, 24081861, 25907713, 31328266). This variant is not present in population databases (gnomAD no frequency). This variant, c.1566_1568del, results in the deletion of 1 amino acid(s) of the CLCN5 protein (p.Val523del), but otherwise preserves the integrity of the reading frame. (less)
Pathogenic (May 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003917789.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: CLCN5: PM2, PM6, PS3:Moderate, PS4:Moderate, PM4:Supporting, PP4 Number of individuals with the variant: 2

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects CLCN5 function (PMID: 19546591, 33987651). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant is also known as 523delVal, p.V592_V593delinsV, or p.Val522del. This variant has been observed in individuals with Dent disease (PMID: 19546591, 24081861, 25907713, 31328266). This variant is not present in population databases (gnomAD no frequency). This variant, c.1566_1568del, results in the deletion of 1 amino acid(s) of the CLCN5 protein (p.Val523del), but otherwise preserves the integrity of the reading frame.

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
Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function.	Durán M	Human molecular genetics	2021	PMID: 33987651
Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system.	Rao J	Clinical genetics	2019	PMID: 31328266
Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1.	Mansour-Hendili L	Human mutation	2015	PMID: 25907713
Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe/USA: genetic and clinical studies of 86 unrelated patients with low-molecular-weight proteinuria.	Sekine T	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2014	PMID: 24081861
Mutational analysis of CLC-5, cofilin and CLC-4 in patients with Dent's disease.	Wu F	Nephron. Physiology	2009	PMID: 19546591

Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001127898.4(CLCN5):c.1773TGT[1] (p.Val593del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...