ClinVar Genomic variation as it relates to human health
NM_017433.5(MYO3A):c.4681C>T (p.Arg1561Ter)
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.
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(1); Likely pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017433.5(MYO3A):c.4681C>T (p.Arg1561Ter)
Variation ID: 631635 Accession: VCV000631635.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10p12.1 10: 26203058 (GRCh38) [ NCBI UCSC ] 10: 26491987 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 27, 2019 Feb 14, 2024 Oct 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017433.5:c.4681C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_059129.3:p.Arg1561Ter nonsense NC_000010.11:g.26203058C>T NC_000010.10:g.26491987C>T NG_011635.1:g.273986C>T LRG_1354:g.273986C>T LRG_1354t1:c.4681C>T LRG_1354p1:p.Arg1561Ter - Protein change
- R1561*
- Other names
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- Canonical SPDI
- NC_000010.11:26203057:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00012
Exome Aggregation Consortium (ExAC) 0.00014
The Genome Aggregation Database (gnomAD) 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00022
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054
- Links
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 | ||
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HI score
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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. |
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MYO3A | - | - |
GRCh38 GRCh37 |
720 | 735 |
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. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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May 14, 2020 | RCV000778282.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 8, 2023 | RCV001564739.8 |
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. |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 30
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914458.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The MYO3A c.4681C>T (p.Arg1561Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg1561Ter variant has been reported in … (more)
The MYO3A c.4681C>T (p.Arg1561Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg1561Ter variant has been reported in one individual with hearing loss who was part of a study evaluating response to cochlear implantation. This individual carried the p.Arg1561Ter variant in a heterozygous state and also carried a second missense variant, but it is not clear if this second variant was present in cis or trans relative to p.Arg1561Ter (Wu et al. 2015). Control data are unavailable for this variant which is reported at a frequency of 0.00114 in the African American population from the Exome Sequencing Project. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Based on the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for recessively inherited nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Deafness, autosomal recessive 30
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251548.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The MYO3A c.4681C>T (p.R1561*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been reported in the compound heterozygous … (more)
The MYO3A c.4681C>T (p.R1561*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been reported in the compound heterozygous state in one individual with profound sensorineural hearing impairment (PMID: 26166082). (less)
Number of individuals with the variant: 1
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Uncertain significance
(May 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 30
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425370.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Comment:
This nonsense variant results in a premature stop codon within the last 50 base pairs of the penultimate exon of the gene, likely leading to … (more)
This nonsense variant results in a premature stop codon within the last 50 base pairs of the penultimate exon of the gene, likely leading to a transcript that escapes nonsense-mediated decay and resulting in a truncated protein product. The function of the region predicted to be missing in the truncated protein is unclear at this time. MYO3A c.4681C>T has been previously reported in an individual with hearing loss, who also carried a missense variant in this gene. This MYO3A variant (rs138593211) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the East Asian subpopulation (gnomAD: 20/19954 alleles; 0.1%, no homozygotes). This patient's ethnicity is reported to be Pacific Islander. This variant has been reported in ClinVar. Due to insufficient evidence, we consider the clinical significance of c.4681C>T to be uncertain at this time. (less)
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Uncertain significance
(Dec 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001787948.3
First in ClinVar: Aug 19, 2021 Last updated: Mar 04, 2023 |
Comment:
Observed in a patient with hearing loss in published literature (Wu et al., 2015); Nonsense variant predicted to result in protein truncation, although pathogenic loss-of-function … (more)
Observed in a patient with hearing loss in published literature (Wu et al., 2015); Nonsense variant predicted to result in protein truncation, although pathogenic loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 26166082) (less)
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Uncertain significance
(Jun 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 30
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003817824.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003296718.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1561*) in the MYO3A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg1561*) in the MYO3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO3A are known to be pathogenic (PMID: 12032315, 23990876). This variant is present in population databases (rs138593211, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 26166082). ClinVar contains an entry for this variant (Variation ID: 631635). For these reasons, this variant has been classified as Pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Identifying Children With Poor Cochlear Implantation Outcomes Using Massively Parallel Sequencing. | Wu CC | Medicine | 2015 | PMID: 26166082 |
Diagnostic application of targeted resequencing for familial nonsyndromic hearing loss. | Choi BY | PloS one | 2013 | PMID: 23990876 |
From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. | Walsh T | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 12032315 |
Text-mined citations for rs138593211 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.