ClinVar Genomic variation as it relates to human health
NM_016239.4(MYO15A):c.4198G>A (p.Val1400Met)
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.4198G>A (p.Val1400Met)
Variation ID: 632271 Accession: VCV000632271.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p11.2 17: 18131523 (GRCh38) [ NCBI UCSC ] 17: 18034837 (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 Jul 27, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016239.4:c.4198G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057323.3:p.Val1400Met missense NC_000017.11:g.18131523G>A NC_000017.10:g.18034837G>A NG_011634.2:g.27818G>A - Protein change
- V1400M
- Other names
- NM_016239.4(MYO15A):c.4198G>A
- Canonical SPDI
- NC_000017.11:18131522:G:A
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00006
- 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
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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 |
3015 | 3160 |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 17, 2022 | RCV000779207.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 4, 2020 | RCV000825533.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV001561220.6 | |
Pathogenic (1) |
reviewed by expert panel
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Jul 27, 2021 | RCV002233817.1 |
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
(Jul 27, 2021)
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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: SCV002512125.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
The allele frequency of the c.4198G>A (p.Val1400Met) variant in the MYO15A gene is 0.01980% (7/35356) of African/African-American chromosomes by gnomAD. This variant has been reported … (more)
The allele frequency of the c.4198G>A (p.Val1400Met) variant in the MYO15A gene is 0.01980% (7/35356) of African/African-American chromosomes by gnomAD. This variant has been reported to segregate with hearing loss in at least 3 separate families (PP1_Strong; PMIDs: 27870113, 20642360; Partners LMM internal data SCV000966848.2). This variant has been detected in 10 probands with nonsyndromic hearing loss. For 2 of those probands, a pathogenic or suspected-pathogenic variant was observed in trans, in 1 a rare variant of unknown significance was observed in trans, and in 7 the variant was observed in the homozygous state (PM3_Strong; PMIDs: 27870113, 20642360; Partners LMM internal data SCV000966848.2). Additionally, the REVEL computational prediction analysis tool produced a score of 0.891, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM3_Strong, PP3. (less)
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Pathogenic
(Oct 10, 2018)
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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: SCV000915748.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The MYO15A c.4198G>A (p.Val1400Met) variant has been reported in two studies and is found in a total of 39 probands with hearing loss, including 27 … (more)
The MYO15A c.4198G>A (p.Val1400Met) variant has been reported in two studies and is found in a total of 39 probands with hearing loss, including 27 probands with hearing loss from seven families of Turkish or Brazilian origin who carried the variant in a homozygous state and 12 probands from two Brazilian families who carried the variant in a compound heterozygous state with a second missense variant (Cengiz et al. 2010; Manzoli et al. 2016). Segregation analysis in one Turkish family showed both affected siblings to be homozygous for the p.Val1400Met variant, while an unaffected sibling and both unaffected parents were heterozygous. The p.Val1400Met variant was found in a heterozygous state in one of 20 controls and is reported at a frequency of 0.00020 in the Latino population of the Genome Aggregation Database. Based on the evidence, the p.Val1400Met variant is classified as pathogenic for the recessive form of 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
(Sep 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966848.2
First in ClinVar: Aug 26, 2019 Last updated: May 29, 2021 |
Comment:
The p.Val1400Met variant in MYO15A has been reported in 10 probands with sensorineural hearing loss, including 7 homozygous individuals, 2 individuals who were compound heterozygous … (more)
The p.Val1400Met variant in MYO15A has been reported in 10 probands with sensorineural hearing loss, including 7 homozygous individuals, 2 individuals who were compound heterozygous for a variant of uncertain significance, and 1 individual who was confirmed to have a nonsense variant present in trans (Cengiz 2010 PMID:20642360, Manzoli 2016 PMID:27870113, LMM unpublished data). Furthermore, the variant segregated with hearing loss in 12 affected members of 7 families, including 2 compound heterozygous individuals (Cengiz 2010 PMID:20642360, Manzoli 2016 PMID:27870113, LMM unpublished data). This variant has also been identified in 0.02% (7/35356) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity on its own. In summary, although additional studies are required to fully establish its clinical significance, the p.Val1400Met variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PM3, PP3, PM2_Supporting. (less)
Number of individuals with the variant: 4
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Pathogenic
(-)
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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:
maternal
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Molecular Diagnosis Center for Deafness
Accession: SCV001984898.1
First in ClinVar: Apr 26, 2022 Last updated: Apr 26, 2022 |
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 17, 2022)
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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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810282.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 06, 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: SCV001783775.4
First in ClinVar: Aug 14, 2021 Last updated: Nov 25, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 35346193, 26242193, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 35346193, 26242193, 27375115, 34652575, 20642360, 27870113, 33398081) (less)
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Likely pathogenic
(Dec 10, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002017857.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 19, 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: SCV004298140.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1400 of the MYO15A protein (p.Val1400Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1400 of the MYO15A protein (p.Val1400Met). This variant is present in population databases (rs749136456, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 20642360, 27870113, 33398081, 35346193). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 632271). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO15A protein function. 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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Analysis of the genotype-phenotype correlation of MYO15A variants in Chinese non-syndromic hearing loss patients. | Fu Y | BMC medical genomics | 2022 | PMID: 35346193 |
A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing. | Hirsch Y | European journal of human genetics : EJHG | 2021 | PMID: 33398081 |
Targeted Resequencing of Deafness Genes Reveals a Founder MYO15A Variant in Northeastern Brazil. | Manzoli GN | Annals of human genetics | 2016 | PMID: 27870113 |
Recurrent and private MYO15A mutations are associated with deafness in the Turkish population. | Cengiz FB | Genetic testing and molecular biomarkers | 2010 | PMID: 20642360 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/429026a9-22bf-43c4-8735-e5fb87686291 | - | - | - | - |
Text-mined citations for rs749136456 ...
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.