ClinVar Genomic variation as it relates to human health
NM_016239.4(MYO15A):c.1137del (p.Tyr380fs)
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_016239.4(MYO15A):c.1137del (p.Tyr380fs)
Variation ID: 500061 Accession: VCV000500061.25
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 17p11.2 17: 18119934 (GRCh38) [ NCBI UCSC ] 17: 18023248 (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 Apr 2, 2018 Apr 6, 2024 Mar 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016239.4:c.1137del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057323.3:p.Tyr380fs frameshift NM_016239.3:c.1137del NC_000017.11:g.18119937del NC_000017.10:g.18023251del NG_011634.2:g.16232del - Protein change
- Y380fs
- Other names
- NM_016239.4(MYO15A):c.1137del
- p.Tyr380fs
- Canonical SPDI
- NC_000017.11:18119933:CCCC:CCC
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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.
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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
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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
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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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MYO15A | - | - |
GRCh38 GRCh37 |
3026 | 3171 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000597925.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2017 | RCV000779205.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 2, 2020 | RCV001195292.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 12, 2021 | RCV001375258.2 | |
Likely pathogenic (1) |
reviewed by expert panel
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Mar 20, 2024 | RCV002232560.2 |
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
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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
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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
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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
(Mar 20, 2024)
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reviewed by expert panel
Method: curation
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Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV002512114.2
First in ClinVar: May 16, 2022 Last updated: Apr 06, 2024 |
Comment:
The c.1137del (p.Tyr380fsTer64) variant in MYO15A is frameshift variant in biologically relevant exon 2/66 that is predicted to lead to a truncated or absent protein … (more)
The c.1137del (p.Tyr380fsTer64) variant in MYO15A is frameshift variant in biologically relevant exon 2/66 that is predicted to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.0.0 is 210/1179974 alleles (0.0001780 or 0.0178 %) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This variant has been detected in 3 individuals with nonsyndromic hearing loss. For each of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, but phase was not confirmed (p.Lys1003fsTer55, p.Glu209Ter, p.Arg3134Ter; PMIDs: 23208854, 28000701, 31980526; 1.5 pts. PM3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: (PVS1, PM3; Version 1; 3/20/2024). (less)
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Pathogenic
(Feb 15, 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: SCV000705841.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 3
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915746.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The MYO15A c.1137delC (p.Tyr380MetfsTer64) variant is a frameshift variant that is predicted to result in premature termination of the protein. This variant has been reported … (more)
The MYO15A c.1137delC (p.Tyr380MetfsTer64) variant is a frameshift variant that is predicted to result in premature termination of the protein. This variant has been reported in a compound heterozygous state along with a second null variant in three individuals with hearing loss (Schrauwen et al. 2013; Neveling et al. 2013; Vona et al. 2014). The individual identified in the Vona et al. (2014) study also carried the c.7C>G (p.Gln3Glu) missense variant in the MYH9 gene. The p.Tyr380MetfsTer64 variant was absent from nine normal hearing controls, but is reported at a frequency of 0.00038 in the European American population of the Exome Sequencing Project. Based on the evidence and due to the potential impact of frameshift variants, the p.Tyr380MetfsTer64 is classified as likely pathogenic for autosomal recessive 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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Pathogenic
(Apr 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365603.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
The p.Tyr380MetfsX64 variant in MYO15A has been previously reported in at least 3 individuals with hearing loss who were compound heterozygous for a second truncating … (more)
The p.Tyr380MetfsX64 variant in MYO15A has been previously reported in at least 3 individuals with hearing loss who were compound heterozygous for a second truncating MYO15A variant (Neveling 2013, Schrauwen 2013, Vona 2014, Zazo Seco 2017, Hou 2020). This variant has been identified in 0.02% (26/128476) of European chromosomes by gnomad chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 380 and leads to a premature termination codon 64 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYO15A gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong. (less)
Number of individuals with the variant: 2
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Pathogenic
(Nov 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 3
Affected status: yes
Allele origin:
unknown
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001244797.2
First in ClinVar: May 04, 2020 Last updated: Sep 18, 2020 |
Comment:
A heterozygous frameshift deletion variant, NM_016239.3(MYO15A):c.1137delC, has been identified in exon 2 of 66 of the MYO15A gene. This deletion is predicted to create a … (more)
A heterozygous frameshift deletion variant, NM_016239.3(MYO15A):c.1137delC, has been identified in exon 2 of 66 of the MYO15A gene. This deletion is predicted to create a frameshift starting at amino acid position 380, introducing a stop codon 64 residues downstream, NP_057323.3(MYO15A):p.(Tyr380Metfs*64). This variant is predicted to result in loss of protein function either through truncation (loss of majority of the protein, including all functional domains) or nonsense-mediated decay. The variant is present in the gnomAD database at a frequency of 0.01% (28 heterozygotes) andhas been previously described as a compound heterozygote with a second truncating variant in two patients with hearing loss (Schrauwen, I., et al. (2013), Vona, B. et al. (2014)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Number of individuals with the variant: 2
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Pathogenic
(Apr 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
germline
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Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Accession: SCV001571736.2
First in ClinVar: Apr 29, 2021 Last updated: Apr 29, 2021 |
Comment:
PVS1_Very strong, PS1_Strong, PM2_Supporting, PP1_Supporting
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Pathogenic
(Jan 22, 2024)
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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: SCV003441730.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr380Metfs*64) in the MYO15A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr380Metfs*64) in the MYO15A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs769260536, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with MYO15A-related conditions (PMID: 23208854, 24123792). This variant is also known as c.1134delC. ClinVar contains an entry for this variant (Variation ID: 500061). 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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Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands. | Zazo Seco C | European journal of human genetics : EJHG | 2017 | PMID: 28000701 |
Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations. | Vona B | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24875298 |
A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases. | Neveling K | Human mutation | 2013 | PMID: 24123792 |
A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR-based approach and next generation sequencing. | Schrauwen I | American journal of medical genetics. Part A | 2013 | PMID: 23208854 |
Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing. | Nal N | Human mutation | 2007 | PMID: 17546645 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYO15A | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/507ceb3d-5622-40fb-904a-ccf18ccf0973 | - | - | - | - |
Text-mined citations for rs769260536 ...
HelpRecord last updated Apr 06, 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.