VCV000178290.32 - ClinVar

NM_001692.4(ATP6V1B1):c.1394G>A (p.Arg465His)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(9); Likely benign(1)

11 out of 12 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_001692.4(ATP6V1B1):c.1394G>A (p.Arg465His)

Variation ID: 178290 Accession: VCV000178290.32

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p13.3 2: 70964973 (GRCh38) [ NCBI UCSC ] 2: 71192103 (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	Jun 28, 2015	Jun 22, 2025	Feb 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001692.4:c.1394G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001683.2:p.Arg465His	missense
NC_000002.12:g.70964973G>A
NC_000002.11:g.71192103G>A
NG_008016.1:g.34106G>A
LRG_1176:g.34106G>A
LRG_1176t1:c.1394G>A	LRG_1176p1:p.Arg465His
	P15313:p.Arg465His

... more HGVS ... less HGVS

Protein change

R465H

Other names

Canonical SPDI

NC_000002.12:70964972:G:A

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.

0.00619 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00146

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00254

The Genome Aggregation Database (gnomAD) 0.00275

Trans-Omics for Precision Medicine (TOPMed) 0.00277

The Genome Aggregation Database (gnomAD), exomes 0.00301

The Genome Aggregation Database (gnomAD) 0.00310

Exome Aggregation Consortium (ExAC) 0.00346

1000 Genomes Project 30x 0.00593

1000 Genomes Project 0.00619

Links

ClinGen: CA182049 UniProtKB: P15313#VAR_021015 dbSNP: rs142905621 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.
ATP6V1B1		-	-	GRCh38 GRCh37	715	780

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 specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Dec 10, 2021	RCV000155034.10
Renal tubular acidosis with progressive nerve deafness	Conflicting classifications of pathogenicity (6)	criteria provided, conflicting classifications	Jul 22, 2021	RCV000490321.15
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2025	RCV000885591.16

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.
Benign (Apr 27, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Renal tubular acidosis with progressive nerve deafness Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001297287.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)

Likely benign (Dec 10, 2021) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002050929.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022

Benign (Jul 19, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001950641.2 First in ClinVar: Oct 02, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 27535533, 12579397, 26920127)

Benign (Jan 06, 2025) C Contributing to aggregate classification	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: SCV001029050.7 First in ClinVar: Dec 17, 2019 Last updated: Feb 25, 2025

Benign (Jan 22, 2015) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000226078.6 First in ClinVar: Jun 28, 2015 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP6V1B1 Number of individuals with the variant: 2 Zygosity: Single Heterozygote Sex: mixed

Benign (May 18, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal tubular acidosis with progressive nerve deafness Affected status: no Allele origin: germline	Pars Genome Lab Accession: SCV001736797.2 First in ClinVar: Jun 19, 2021 Last updated: Apr 13, 2025	Sex: mixed

Uncertain significance (Mar 18, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Renal tubular acidosis with progressive nerve deafness Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267215.1 First in ClinVar: May 25, 2017 Last updated: May 25, 2017	Publications: PubMed (1) PubMed: 12579397 Number of individuals with the variant: 1 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean

Benign (Apr 30, 2012) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000204718.4 First in ClinVar: Jan 31, 2015 Last updated: Jun 28, 2015	Comment: Arg465His in Exon 14 of ATP6V1B1: This variant is not expected to have clinical significance because it has been identified in 0.8% (30/3738) of African … (more) Arg465His in Exon 14 of ATP6V1B1: This variant is not expected to have clinical significance because it has been identified in 0.8% (30/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs142905621). (less) Number of individuals with the variant: 7

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Renal tubular acidosis with progressive nerve deafness (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435181.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (1) PubMed: 12579397 Comment: The heterozygous p.Arg465His variant in ATP6V1B1 has been identified in a German individual with renal tubular acidosis and no other potentially causal variant identified in … (more) The heterozygous p.Arg465His variant in ATP6V1B1 has been identified in a German individual with renal tubular acidosis and no other potentially causal variant identified in the gene (PMID: 12579397), but has also been identified in >1% of South Asian chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive renal tubular acidosis. (less) Platform type: WES

Benign (Jul 22, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal tubular acidosis with progressive nerve deafness Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001810282.2 First in ClinVar: Sep 08, 2021 Last updated: Apr 13, 2025	Sex: mixed

Benign (Feb 01, 2025) C Contributing to aggregate classification	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: SCV005892471.4 First in ClinVar: Mar 22, 2025 Last updated: Jun 22, 2025	Comment: ATP6V1B1: BS1, BS2 Number of individuals with the variant: 1

Benign (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Renal tubular acidosis with progressive nerve deafness Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457591.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

Arg465His in Exon 14 of ATP6V1B1: This variant is not expected to have clinical significance because it has been identified in 0.8% (30/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs142905621).

Comment:

The heterozygous p.Arg465His variant in ATP6V1B1 has been identified in a German individual with renal tubular acidosis and no other potentially causal variant identified in the gene (PMID: 12579397), but has also been identified in >1% of South Asian chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive renal tubular acidosis.

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
Confirmation of the ATP6B1 gene as responsible for distal renal tubular acidosis.	Ruf R	Pediatric nephrology (Berlin, Germany)	2003	PMID: 12579397
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP6V1B1	-	-	-	-

Text-mined citations for rs142905621 ...

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 22, 2025

ClinVar Genomic variation as it relates to human health

NM_001692.4(ATP6V1B1):c.1394G>A (p.Arg465His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142905621 ...