ClinVar Genomic variation as it relates to human health
NM_016239.4(MYO15A):c.7124_7127del (p.Asp2375fs)
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.7124_7127del (p.Asp2375fs)
Variation ID: 435919 Accession: VCV000435919.19
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 17p11.2 17: 18052803-18052806 (GRCh37) [ NCBI UCSC ] 17: 18149489-18149492 (GRCh38) [ 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 Aug 28, 2017 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016239.4:c.7124_7127del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057323.3:p.Asp2375fs frameshift NC_000017.11:g.18149492_18149495del NC_000017.10:g.18052806_18052809del NG_011634.2:g.45787_45790del - Protein change
- D2375fs
- Other names
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- Canonical SPDI
- NC_000017.11:18149488:CAGACAG:CAG
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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
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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MYO15A | - | - |
GRCh38 GRCh37 |
3058 | 3203 |
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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May 4, 2020 | RCV000504331.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 17, 2017 | RCV000605806.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626936.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV001653861.9 |
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
(Aug 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 3
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000595891.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital sensorineural hearing impairment
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747639.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Pathogenic
(Aug 17, 2017)
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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: SCV000713100.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Asp2375fs variant in MYO15A has been previously reported in two individual s with hearing loss who also had a second variant on the remaining … (more)
The p.Asp2375fs variant in MYO15A has been previously reported in two individual s with hearing loss who also had a second variant on the remaining copy of MYO15 A (Vona 2014, Sloan-Heggen 2015). This variant has also been identified in 11/1 26686 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs763553435). Although this variant has been see n in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, w hich alters the protein?s amino acid sequence beginning at position 2375 and lea ds to a premature termination codon 41 amino acids downstream. This alteration i s 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 nonsy ndromic sensorineural hearing loss. In summary, this variant meets criteria to b e classified as pathogenic for autosomal recessive hearing loss based on the pre dicted impact on the protein, compound heterozygosity in multiple affected indiv iduals, and low allele frequency in the general population consistent with a rec essive carrier frequency. (less)
Number of individuals with the variant: 2
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Pathogenic
(Mar 02, 2023)
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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: SCV001871034.2
First in ClinVar: Sep 19, 2021 Last updated: May 06, 2023 |
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; Observed … (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; Observed in 0.0043% (12/280936 alleles) in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24875298, 26969326, 32860223) (less)
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Pathogenic
(Jan 18, 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: SCV002246049.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asp2375Valfs*41) 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.Asp2375Valfs*41) 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 (rs780170125, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 24875298, 26969326, 32860223). ClinVar contains an entry for this variant (Variation ID: 435919). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769301.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 35 of 66). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. More than 10 NMD-predicted variants have been reported as likely pathogenic/pathogenic (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least 3 unrelated patients with hearing loss (ClinVar, PMID: 24875298). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Autosomal recessive nonsyndromic hearing loss 3
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002075196.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant interpreted as Likely pathogenic and reported on 06-28-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpreted as Likely pathogenic and reported on 06-28-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Sensorineural hearing loss disorder (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2021-06-28
Testing laboratory interpretation: Likely pathogenic
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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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Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non-syndromic hearing loss detected by gene panel NGS and whole-exome sequencing. | Safka Brozkova D | Clinical genetics | 2020 | PMID: 32860223 |
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
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 |
Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing. | Nal N | Human mutation | 2007 | PMID: 17546645 |
Text-mined citations for rs780170125 ...
HelpRecord last updated Feb 20, 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.