NM_001127898.4(CLCN5):c.1A>G (p.Met1Val) AND Dent disease type 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 6, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002472296.1

Allele description [Variation Report for NM_001127898.4(CLCN5):c.1A>G (p.Met1Val)]

NM_001127898.4(CLCN5):c.1A>G (p.Met1Val)

Gene:

CLCN5:chloride voltage-gated channel 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.23

Genomic location:

Preferred name:

NM_001127898.4(CLCN5):c.1A>G (p.Met1Val)

HGVS:

NC_000023.11:g.49925299A>G
NG_007159.3:g.7684A>G
NM_001127898.4:c.1A>GMANE SELECT
NM_001127899.4:c.1A>G
NM_001272102.2:c.1A>G
NP_001121370.1:p.Met1Val
NP_001121371.1:p.Met1Val
NP_001259031.1:p.Met1Val
NC_000023.10:g.49689909A>G
NM_001127898.3:c.1A>G

Protein change:

M1V

Molecular consequence:

NM_001127898.4:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001127899.4:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001272102.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001127898.4:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127899.4:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001272102.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dent disease type 1
Synonyms:: NEPHROLITHIASIS, HYPERCALCIURIC, X-LINKED; Nephrolithiasis, hypercalciuria X-linked; Urolithiasis, hypercalciuric X-linked; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010225; MedGen: C1848336; Orphanet: 1652; Orphanet: 93622; OMIM: 300009

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002769432	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 6, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25001568, 28580211, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002769432

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 6, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Complexity of the 5'UTR region of the CLCN5 gene: eleven 5'UTR ends are differentially expressed in the human kidney.

Tosetto E, Casarin A, Salviati L, Familiari A, Lieske JC, Anglani F.

BMC Med Genomics. 2014 Jul 7;7:41. doi: 10.1186/1755-8794-7-41.

PubMed [citation]

PMID:: 25001568
PMCID:: PMC4105828

Dent disease: Same CLCN5 mutation but different phenotypes in two brothers in China.

Zhang H, Wang F, Xiao H, Yao Y.

Intractable Rare Dis Res. 2017 May;6(2):114-118. doi: 10.5582/irdr.2017.01019.

PubMed [citation]

PMID:: 28580211
PMCID:: PMC5451742

See all PubMed Citations (3)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769432.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Dent disease (MIM#300009), hypophosphatemic rickets (MIM#300554), nephrolithiasis type I (MIM#310468) and low molecular weight proteinuria with hypercalciuria and nephrocalcinosis (MIM#308990). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity, with intra- and inter-familial phenotypic variability previously reported (PMID: 28580211, OMIM). (I) 0207 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG) however, CLCN5 has alternative 5’UTR exons which results in multiple transcripts and isoforms with alternative start sites (PMID: 25001568). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 0705 - No other start-loss variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 3, 2023

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