VCV000217791.7 - ClinVar

NM_004366.6(CLCN2):c.1412G>A (p.Arg471His)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic
Likely pathogenic (2)

2 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004366.6(CLCN2):c.1412G>A (p.Arg471His)

Variation ID: 217791 Accession: VCV000217791.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q27.1 3: 184354643 (GRCh38) [ NCBI UCSC ] 3: 184072431 (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	Nov 9, 2015	Oct 8, 2024	Apr 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004366.6:c.1412G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004357.3:p.Arg471His	missense
NM_001171087.3:c.1397-36G>A		intron variant
NM_001171088.3:c.1280G>A	NP_001164559.1:p.Arg427His	missense
NM_001171089.3:c.1412G>A	NP_001164560.1:p.Arg471His	missense
NC_000003.12:g.184354643C>T
NC_000003.11:g.184072431C>T
NG_016422.1:g.11961G>A

... more HGVS ... less HGVS

Protein change

R471H, R427H

Other names

Canonical SPDI

NC_000003.12:184354642:C:T

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA347614 dbSNP: rs771507094 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.
CLCN2		-	-	GRCh38 GRCh37	692	753

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.
Leukoencephalopathy with mild cerebellar ataxia and white matter edema	not provided (1)	no classification provided	-	RCV000201810.10
not provided	Likely pathogenic (1)	criteria provided, single submitter	Feb 1, 2022	RCV002277555.9
Familial hyperaldosteronism type II	Likely pathogenic (1)	criteria provided, single submitter	Apr 4, 2024	RCV003992233.3
CLCN2-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 31, 2024	RCV004553102.3

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Apr 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial hyperaldosteronism type II	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004809540.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Feb 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV002567558.2 First in ClinVar: Aug 29, 2022 Last updated: Mar 04, 2023	Comment: show Published functional studies demonstrate a decrease in CLCN2 current activation (Gaitan-Penas et al. 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 28905383, 28746943) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jan 31, 2024) N Not contributing to aggregate classification	no assertion criteria provided	CLCN2-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004796850.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show The CLCN2 c.1412G>A variant is predicted to result in the amino acid substitution p.Arg471His. This variant has been reported in the homozygous state in one patient with gait-speech difficulty, dysarthria, nystagmus, ataxic gait, dysmetria and brain MRI findings consistent with CLCN2-related disease (Patient 1, Zeydan et al. 2017. PubMed ID: 28746943). This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD. In vitro functional characterization showed that this variant leads to significantly reduced current when compared to controls (Gaitán-Peñas. 2017. PubMed ID: 28905383). This variant is interpreted as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

not provided (-) N Not contributing to aggregate classification	no classification provided	Leukoencephalopathy with mild cerebellar ataxia and white matter edema	GeneReviews Accession: SCV000256588.2 First in ClinVar: Nov 09, 2015 Last updated: Oct 01, 2022	Publications: BookShelf: NBK326661 BookShelf: NBK326661 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes Observation 1 Collection method: literature only Allele origin: germline Affected status: yes

Comment:

Published functional studies demonstrate a decrease in CLCN2 current activation (Gaitan-Penas et al. 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 28905383, 28746943)

Comment:

The CLCN2 c.1412G>A variant is predicted to result in the amino acid substitution p.Arg471His. This variant has been reported in the homozygous state in one patient with gait-speech difficulty, dysarthria, nystagmus, ataxic gait, dysmetria and brain MRI findings consistent with CLCN2-related disease (Patient 1, Zeydan et al. 2017. PubMed ID: 28746943). This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD. In vitro functional characterization showed that this variant leads to significantly reduced current when compared to controls (Gaitán-Peñas. 2017. PubMed ID: 28905383). This variant is interpreted as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
CLCN2-Related Leukoencephalopathy.	Adam MP	-	2021	PMID: 26539602

Text-mined citations for rs771507094 ...

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 Jun 14, 2026