The heterozygous p.Val586Met variant, sometimes called p.Val631Met due to a difference in cDNA numbering, in ATP2B2 has been identified in at least 5 individuals with hearing loss, including 3 siblings from 1 family (PMID: 15829536). Of note, 2 additional siblings in the same family did not have this variant and are less severely affected by disease. All 5 siblings were reported to be homozygous for a separate, causal variant in CDH23 (PMID: 15829536). This variant has also been identified in >4% of Latino chromosomes and 22 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Val586Met variant may have a mild impact on protein function (PMID: 22047666). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive deafness but may modify disease.
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Benign
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 4
- First in ClinVar:
- Jan 6, 2017
- Most recent Submission:
- Apr 23, 2023
- Last evaluated:
- Jan 1, 2023
- Accession:
- VCV000017801.9
- Variation ID:
- 17801
- Description:
- single nucleotide variant
Help
NM_001001331.4(ATP2B2):c.1891G>A (p.Val631Met)
- Allele ID
- 32840
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 3p25.3
- Genomic location
- 3: 10359892 (GRCh38) GRCh38 UCSC
- 3: 10401576 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001001331.4:c.1891G>A MANE Select NP_001001331.1:p.Val631Met missense NM_001330611.3:c.1756G>A NP_001317540.1:p.Val586Met missense NM_001353564.1:c.1756G>A NP_001340493.1:p.Val586Met missense NM_001363862.1:c.1756G>A NP_001350791.1:p.Val586Met missense NM_001683.5:c.1756G>A NP_001674.2:p.Val586Met missense NC_000003.12:g.10359892C>T NC_000003.11:g.10401576C>T NG_012046.2:g.353140G>A - Protein change
- V586M, V631M
- Other names
- -
- Canonical SPDI
- NC_000003.12:10359891:C:T
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- 0.00799 (T)
- Allele frequency
- The Genome Aggregation Database (gnomAD) 0.00554
- Trans-Omics for Precision Medicine (TOPMed) 0.00823
- 1000 Genomes Project 0.00799
- Links
- ClinGen: CA127431
- OMIM: 108733.0001
- dbSNP: rs61736451
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Benign | 2 | criteria provided, multiple submitters, no conflicts | Jan 1, 2023 | RCV000954243.7 | |
| Benign | 1 | criteria provided, single submitter | - | RCV001258253.1 | |
| risk factor | 1 | no assertion criteria provided | Apr 14, 2005 | RCV000019379.25 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Benign
(-)
|
criteria provided, single submitter
Method: research
|
Agenesis of the corpus callosum with peripheral neuropathy
Affected status: yes
Allele origin:
germline
|
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001435167.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The heterozygous p.Val586Met variant, sometimes called p.Val631Met due to a difference in cDNA numbering, in ATP2B2 has been identified in at least 5 individuals with … (more)
The heterozygous p.Val586Met variant, sometimes called p.Val631Met due to a difference in cDNA numbering, in ATP2B2 has been identified in at least 5 individuals with hearing loss, including 3 siblings from 1 family (PMID: 15829536). Of note, 2 additional siblings in the same family did not have this variant and are less severely affected by disease. All 5 siblings were reported to be homozygous for a separate, causal variant in CDH23 (PMID: 15829536). This variant has also been identified in >4% of Latino chromosomes and 22 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Val586Met variant may have a mild impact on protein function (PMID: 22047666). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive deafness but may modify disease. (less)
|
|
|
Benign
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001100863.4
First in ClinVar: Dec 17, 2019 Last updated: Feb 07, 2023 |
|
|
|
Benign
(Jan 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV003916408.1
First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023 |
Number of individuals with the variant: 1
|
|
|
risk factor
(Apr 14, 2005)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL RECESSIVE 12, MODIFIER OF
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039669.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017 |
Comment on evidence:
In 3 of 5 sibs, born of consanguineous parents, with autosomal recessive deafness (DFNB12; 601386) caused by a homozygous phe1888-to-ser substitution in the CDH23 gene … (more)
In 3 of 5 sibs, born of consanguineous parents, with autosomal recessive deafness (DFNB12; 601386) caused by a homozygous phe1888-to-ser substitution in the CDH23 gene (F1888S; 605516.0010), Schultz et al. (2005) identified a heterozygous 2075G-A transition in exon 12 of the ATP2B2 gene, resulting in a val586-to-met (V586M) substitution. The 3 sibs heterozygous for V586M had severe to profound hearing loss affecting all frequencies, whereas the other 2 sibs had high-frequency hearing loss. Schultz et al. (2005) suggested that V586M modifies the severity of sensorineural hearing loss. Lek et al. (2016) questioned the validity of this variant as a modifier of the severity of deafness because it has a high allele frequency (0.0467) in the Latino population in the ExAC database. (less)
|
Functional evidence
Help| 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. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of protein-coding genetic variation in 60,706 humans. | Lek M | Nature | 2016 | PMID: 27535533 |
| Mutations in PMCA2 and hereditary deafness: a molecular analysis of the pump defect. | Giacomello M | Cell calcium | 2011 | PMID: 22047666 |
| Modification of human hearing loss by plasma-membrane calcium pump PMCA2. | Schultz JM | The New England journal of medicine | 2005 | PMID: 15829536 |
Text-mined citations for rs61736451...
HelpThese 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 Apr 23, 2023