ClinVar Genomic variation as it relates to human health
NM_004999.4(MYO6):c.826C>T (p.Arg276Ter)
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(6); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004999.4(MYO6):c.826C>T (p.Arg276Ter)
Variation ID: 164634 Accession: VCV000164634.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q14.1 6: 75844906 (GRCh38) [ NCBI UCSC ] 6: 76554623 (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 Feb 2, 2015 May 1, 2024 Nov 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004999.4:c.826C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004990.3:p.Arg276Ter nonsense NM_001300899.2:c.826C>T NP_001287828.1:p.Arg276Ter nonsense NM_001368136.1:c.826C>T NP_001355065.1:p.Arg276Ter nonsense NM_001368137.1:c.826C>T NP_001355066.1:p.Arg276Ter nonsense NM_001368138.1:c.811C>T NP_001355067.1:p.Arg271Ter nonsense NM_001368865.1:c.826C>T NP_001355794.1:p.Arg276Ter nonsense NM_001368866.1:c.826C>T NP_001355795.1:p.Arg276Ter nonsense NR_160538.1:n.1058C>T non-coding transcript variant NC_000006.12:g.75844906C>T NC_000006.11:g.76554623C>T NG_009934.2:g.100714C>T LRG_438:g.100714C>T LRG_438t1:c.826C>T LRG_438p1:p.Arg276Ter - Protein change
- R276*, R271*
- Other names
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- Canonical SPDI
- NC_000006.12:75844905: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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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MYO6 | - | - |
GRCh38 GRCh37 |
738 | 766 |
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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Pathogenic (1) |
criteria provided, single submitter
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Jan 27, 2014 | RCV000151469.4 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Nov 26, 2022 | RCV000599449.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763565.2 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 27, 2021 | RCV001753534.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 22, 2022 | RCV002250575.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2023 | RCV004019820.1 |
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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Pathogenic
(May 10, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000708497.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 22
Autosomal recessive nonsyndromic hearing loss 37
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894396.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jan 27, 2014)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000199516.4
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Comment:
The Arg276X variant in MYO6 has not been previously reported in individuals with hearing loss or in large population studies. This variant introduces a prematur … (more)
The Arg276X variant in MYO6 has not been previously reported in individuals with hearing loss or in large population studies. This variant introduces a prematur e stop codon at position 276 leading to either a truncated or absent protein. I n summary, this variant meets our criteria for pathogenicity (http://pcpgm.partn ers.org/LMM). (less)
Number of individuals with the variant: 1
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 37
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521636.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense): predicted to result in a … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000164634 / PMID: 26969326). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
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Uncertain significance
(Dec 21, 2020)
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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: SCV000709820.4
First in ClinVar: Apr 02, 2018 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in patients with hearing loss referred for genetic testing at GeneDx and in published literature (Sloan-Heggen et al., 2016); This variant is associated with the following publications: (PMID: 29044474, 26969326, 31589614) (less)
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Pathogenic
(Nov 26, 2022)
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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: SCV002228138.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs727503326, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg276*) in the MYO6 gene. It … (more)
This variant is present in population databases (rs727503326, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg276*) in the MYO6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO6 are known to be pathogenic (PMID: 12687499, 18348273, 23767834, 25999546, 30582396). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 26969326). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 164634). (less)
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Likely pathogenic
(Jan 05, 2022)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502565.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
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Pathogenic
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004953976.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.826C>T (p.R276*) alteration, located in exon 10 (coding exon 9) of the MYO6 gene, consists of a C to T substitution at nucleotide position … (more)
The c.826C>T (p.R276*) alteration, located in exon 10 (coding exon 9) of the MYO6 gene, consists of a C to T substitution at nucleotide position 826. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 276. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (4/251012) total alleles studied. The highest observed frequency was 0.009% (3/34560) of Latino alleles. This variant has been reported in one individual with a personal and family history of hearing loss (Wu, 2022). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Oct 27, 2021)
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no assertion criteria provided
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 22
Affected status: yes
Allele origin:
paternal
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001994794.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
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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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Molecular diagnose of a large hearing loss population from China by targeted genome sequencing. | Wu J | Journal of human genetics | 2022 | PMID: 35982127 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Targeted Mutation Analysis of the SLC26A4, MYO6, PJVK and CDH23 Genes in Iranian Patients with AR Nonsyndromic Hearing Loss. | Alimardani M | Fetal and pediatric pathology | 2019 | PMID: 30582396 |
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
Massively parallel DNA sequencing successfully identified seven families with deafness-associated MYO6 mutations: the mutational spectrum and clinical characteristics. | Miyagawa M | The Annals of otology, rhinology, and laryngology | 2015 | PMID: 25999546 |
Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing. | Yang T | Orphanet journal of rare diseases | 2013 | PMID: 23767834 |
A novel nonsense mutation in MYO6 is associated with progressive nonsyndromic hearing loss in a Danish DFNA22 family. | Sanggaard KM | American journal of medical genetics. Part A | 2008 | PMID: 18348273 |
Mutations of MYO6 are associated with recessive deafness, DFNB37. | Ahmed ZM | American journal of human genetics | 2003 | PMID: 12687499 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYO6 | - | - | - | - |
Text-mined citations for rs727503326 ...
HelpRecord last updated May 08, 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.