ClinVar Genomic variation as it relates to human health
NM_004999.4(MYO6):c.2751dup (p.Gln918fs)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004999.4(MYO6):c.2751dup (p.Gln918fs)
Variation ID: 523937 Accession: VCV000523937.16
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 6q14.1 6: 75890140-75890141 (GRCh38) [ NCBI UCSC ] 6: 76599857-76599858 (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 21, 2018 Apr 15, 2024 Jul 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004999.4:c.2751dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004990.3:p.Gln918fs frameshift NM_004999.4:c.2751dupA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001300899.2:c.2751dup NP_001287828.1:p.Gln918fs frameshift NM_001368136.1:c.2751dup NP_001355065.1:p.Gln918fs frameshift NM_001368137.1:c.2751dup NP_001355066.1:p.Gln918fs frameshift NM_001368138.1:c.2736dup NP_001355067.1:p.Gln913fs frameshift NM_001368865.1:c.2751dup NP_001355794.1:p.Gln918fs frameshift NM_001368866.1:c.2751dup NP_001355795.1:p.Gln918fs frameshift NM_004999.3:c.2751dupA NR_160538.1:n.3076dup non-coding transcript variant NC_000006.12:g.75890149dup NC_000006.11:g.76599866dup NG_009934.2:g.145957dup LRG_438:g.145957dup LRG_438t1:c.2751dup LRG_438p1:p.Gln918fs - Protein change
- Q918fs, Q913fs
- Other names
- NM_004999.4(MYO6):c.2751dup
- p.Gln918fs
- Canonical SPDI
- NC_000006.12:75890140:AAAAAAAAA:AAAAAAAAAA
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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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0.00359 (AAAAAAAAAA)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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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 (3) |
criteria provided, multiple submitters, no conflicts
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Oct 10, 2023 | RCV000627419.7 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001543426.3 | |
Likely pathogenic (2) |
reviewed by expert panel
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Jul 25, 2023 | RCV002250426.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002248831.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV003336098.1 | |
MYO6-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Aug 4, 2023 | RCV004527692.1 |
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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Likely pathogenic
(Jul 25, 2023)
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reviewed by expert panel
Method: curation
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Nonsyndromic genetic hearing loss
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV002520697.3 First in ClinVar: Jun 03, 2022 Last updated: Oct 07, 2023 |
Comment:
The c.2751dup (p.Gln918fs) frameshift variant in MYO6 is predicted to cause a premature stop codon in biologically-relevant exon 26 of 35 total exons, leading to … (more)
The c.2751dup (p.Gln918fs) frameshift variant in MYO6 is predicted to cause a premature stop codon in biologically-relevant exon 26 of 35 total exons, leading to a truncated or absent protein in a gene where loss of function is an established mechanism of autosomal dominant hearing loss (PVS1; PMID: 30192042). The highest minor allele frequency in gnomAD v.2.1.1 was 0.048% (52/109484) of European (non-Finnish) population, but was noted to occur in a low complexity region where variant quality was dubious, so BS1 was not applied. It was observed in 2 probands with moderate sensorineural hearing loss, meeting PS4_Supporting (PMID: 25080041, 33297549). In summary, this variant is likely pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: PVS1, PS4_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 7/25/2023). (less)
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Pathogenic
(Sep 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905664.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Clinical Features:
Hearing impairment (present)
Sex: female
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Uncertain significance
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518342.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Nov 09, 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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GeneDx
Accession: SCV000748415.4
First in ClinVar: May 21, 2018 Last updated: Dec 03, 2022 |
Comment:
Frameshift 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; Not … (more)
Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33297549, 30245029, 25080041) (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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DEAFNESS, AUTOSOMAL DOMINANT 22
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046004.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This frameshifting variant in exon 26 of 35 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function … (more)
This frameshifting variant in exon 26 of 35 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous variant in one individual with late-onset progressive, moderate non-syndromic hearing loss (PMID: 25080041). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.032% (76/235680). Based on the available evidence, the c.2751dup (p.Gln918ThrfsTer24) variant is classified as Likely Pathogenic. (less)
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Uncertain significance
(Aug 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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MYO6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004105168.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MYO6 c.2751dupA variant is predicted to result in a frameshift and premature protein termination (p.Gln918Thrfs*24). This variant has been reported in the gnomAD public … (more)
The MYO6 c.2751dupA variant is predicted to result in a frameshift and premature protein termination (p.Gln918Thrfs*24). This variant has been reported in the gnomAD public population database at a subpopulation frequency as high as 0.047% (https://gnomad.broadinstitute.org/variant/6-76599857-G-GA). However, the c.2751dup variant is part of a mononucleotide repeat of nine adenosines, which makes this allele frequency estimate unreliable. This variant has previously been reported as causative in a family with autosomal dominant, progressive, mild to moderate nonsyndromic hearing loss with onset in the fifth decade (Kwon et al. 2014. PubMed ID: 25080041). Despite this family having five affected individuals across two generations, the c.2751dup variant was only reported as being present in one individual with unclear genotype of the other affected and unaffected family members. This variant has also been reported in the heterozygous state in two related patients with autosomal dominant hearing loss, although a potentially causative variant in another gene was also identified (García-García et al 2020. PubMed ID: 33297549). This variant has been detected at PreventionGenetics in two unrelated families; the first with the c.2751dup variant in the heterozygous state in two siblings with hearing loss, and the second with the c.2751dup variant in the homozygous state in a single affected individual with no family history of hearing loss. Frameshift variants in MYO6 are expected to be pathogenic. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Pathogenic
(Oct 10, 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: SCV004531993.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln918Thrfs*24) in the MYO6 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln918Thrfs*24) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal dominant non-syndromic hearing loss (PMID: 25080041). ClinVar contains an entry for this variant (Variation ID: 523937). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic genetic hearing loss
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812588.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in MYO6 is a frameshift variant predicted to cause a premature stop codon, p.(Gln918Thrfs*24) in biologically-relevant-exon 26/35 leading to nonsense mediated decay … (more)
This sequence change in MYO6 is a frameshift variant predicted to cause a premature stop codon, p.(Gln918Thrfs*24) in biologically-relevant-exon 26/35 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (ClinGen). The highest population minor allele frequency in gnomAD v3.1 is 0.007% (1/14,740 alleles) in the Latino/Admixed American population. The prevalence of the variant in individuals with non-syndromic hearing loss is significantly increased compared with the prevalence in controls (Odds ratio 17.2, 95% confidence interval: 1.79 - 165) (Cases: PMID: 25080041, 26969326, 33297549; Controls: gnomAD v3.1 Latino/Admixed American population). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4_Moderate. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: research
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essential tremor
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001761987.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 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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Exome-wide rare variant analysis in familial essential tremor. | Diez-Fairen M | Parkinsonism & related disorders | 2021 | PMID: 33279834 |
Improving the Management of Patients with Hearing Loss by the Implementation of an NGS Panel in Clinical Practice. | García-García G | Genes | 2020 | PMID: 33297549 |
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 |
The effect of novel mutations on the structure and enzymatic activity of unconventional myosins associated with autosomal dominant non-syndromic hearing loss. | Kwon TJ | Open biology | 2014 | PMID: 25080041 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2f4065a0-5a55-4590-a672-f3b6bbcc2ed5 | - | - | - | - |
Text-mined citations for rs551348450 ...
HelpRecord last updated May 27, 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.