A heterozygous in-frame deletion variant was identified in exon 64 of MYO15A, NM_016239.3(MYO15A):c.10250_10252delCCT.This deletionresults in the lossof a serineat codon position 3417, NP_057323.3(MYO15A):p.(Ser3417del). The serine at this position has very high conservation (100 vertebrates, UCSC). It is situated in the FERM domain. This variant is present in the gnomAD population database at a frequency of 0.002%. It has not been previously observed in other clinical cases. Based on current information and in association with the NM_016239.3(MYO15A):c.9371dupA deletion variant, this variant has been classified as LIKELY PATHOGENIC.Parental testingindicates the variants are in trans. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness 3.NB: This variant has been reclassified from Class 3A (VUS with high clinical significance)to Class 4 (likely pathogenic).
ClinVar Genomic variation as it relates to human health
NM_016239.4(MYO15A):c.10247CCT[1] (p.Ser3417del)
Germline
Classification
Help
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.
(6)
Help
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/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_016239.4(MYO15A):c.10247CCT[1] (p.Ser3417del)
Variation ID: 869466 Accession: VCV000869466.29
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 17p11.2 17: 18172185-18172187 (GRCh38) [ NCBI UCSC ] 17: 18075499-18075501 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 4, 2020 Oct 8, 2024 Sep 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_016239.4:c.10247CCT[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057323.3:p.Ser3417del inframe deletion NM_016239.4:c.10250_10252del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_016239.4:c.10250_10252delCCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_016239.3:c.10250_10252delCCT NC_000017.11:g.18172187CCT[1] NC_000017.10:g.18075501CCT[1] NG_011634.2:g.68482CCT[1] - Protein change
- S3417del
- Other names
- -
- Canonical SPDI
- NC_000017.11:18172184:CTCCTCCT:CTCCT
-
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.
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- 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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| MYO15A | - | - |
GRCh38 GRCh37 |
3113 | 3258 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2022 | RCV001089558.4 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 25, 2024 | RCV001759858.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 10, 2024 | RCV004017785.1 |
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
(Aug 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 3
Affected status: yes
Allele origin:
unknown
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001244795.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
A heterozygous in-frame deletion variant was identified in exon 64 of MYO15A, NM_016239.3(MYO15A):c.10250_10252delCCT.This deletionresults in the lossof a serineat codon position 3417, NP_057323.3(MYO15A):p.(Ser3417del). The serine … (more)
A heterozygous in-frame deletion variant was identified in exon 64 of MYO15A, NM_016239.3(MYO15A):c.10250_10252delCCT.This deletionresults in the lossof a serineat codon position 3417, NP_057323.3(MYO15A):p.(Ser3417del). The serine at this position has very high conservation (100 vertebrates, UCSC). It is situated in the FERM domain. This variant is present in the gnomAD population database at a frequency of 0.002%. It has not been previously observed in other clinical cases. Based on current information and in association with the NM_016239.3(MYO15A):c.9371dupA deletion variant, this variant has been classified as LIKELY PATHOGENIC.Parental testingindicates the variants are in trans. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness 3.NB: This variant has been reclassified from Class 3A (VUS with high clinical significance)to Class 4 (likely pathogenic). (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 3
Affected status: unknown
Allele origin:
maternal
|
Molecular Diagnosis Center for Deafness
Accession: SCV001984912.1
First in ClinVar: Apr 27, 2022 Last updated: Apr 27, 2022 |
Number of individuals with the variant: 2
|
|
|
Likely pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 3
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572658.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). This variant leads to inframe deletion located … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). This variant leads to inframe deletion located in a nonrepeat region that it is predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000869466 / PMID: 25792667). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
|
|
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Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004298179.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant, c.10250_10252del, results in the deletion of 1 amino acid(s) of the MYO15A protein (p.Ser3417del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.10250_10252del, results in the deletion of 1 amino acid(s) of the MYO15A protein (p.Ser3417del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760069953, gnomAD 0.04%). This variant has been observed in individual(s) with deafness (PMID: 25792667, 29482514, 30896630, 34265623, 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. This variant is also known as c.10249_10251delTCC (p.F3417del) or c.10245_10247delCTC. ClinVar contains an entry for this variant (Variation ID: 869466). For these reasons, this variant has been classified as Pathogenic. (less)
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|
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Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847413.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Ser3417del variant in MYO15A has been reported in >15 compound heterozygous or homozygous individuals with hearing loss and segregated with disease in at least … (more)
The p.Ser3417del variant in MYO15A has been reported in >15 compound heterozygous or homozygous individuals with hearing loss and segregated with disease in at least 4 affected individuals from 3 families (Miyagawa 2015 PMID: 25792667, Chang 2018 PMID: 29482514, Sun 2019 PMID: 30896630, Xu 2020 PMID: 32802042, Downie 2020 PMID: 31827275, Liang 2021 PMID: 34265623, Chen 2022 PMID: 34974475, Fu 2022 PMID: 35346193, Kim 2022 PMID: 35853923, Ma 2023 PMID: 36597107). It has also been identified in 0.027% (12/44898) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). This variant has also been reported in ClinVar (Variation ID 869466). This variant is a deletion of 1 amino acid at position 3417 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PM4_Supporting. (less)
|
|
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Likely pathogenic
(Sep 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001986243.3
First in ClinVar: Nov 06, 2021 Last updated: Oct 08, 2024 |
Comment:
In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with … (more)
In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25792667, 29482514, 31581539, 31827275, 30896630, 35346193, 34265623, 35853923, 35982127, 36597107, 35939872, 34974475, 32802042, 38297847, 34325055, 38056549, 38860500) (less)
|
Comment:
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). This variant leads to inframe deletion located in a nonrepeat region that it is predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000869466 / PMID: 25792667). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant, c.10250_10252del, results in the deletion of 1 amino acid(s) of the MYO15A protein (p.Ser3417del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760069953, gnomAD 0.04%). This variant has been observed in individual(s) with deafness (PMID: 25792667, 29482514, 30896630, 34265623, 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. This variant is also known as c.10249_10251delTCC (p.F3417del) or c.10245_10247delCTC. ClinVar contains an entry for this variant (Variation ID: 869466). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Ser3417del variant in MYO15A has been reported in >15 compound heterozygous or homozygous individuals with hearing loss and segregated with disease in at least 4 affected individuals from 3 families (Miyagawa 2015 PMID: 25792667, Chang 2018 PMID: 29482514, Sun 2019 PMID: 30896630, Xu 2020 PMID: 32802042, Downie 2020 PMID: 31827275, Liang 2021 PMID: 34265623, Chen 2022 PMID: 34974475, Fu 2022 PMID: 35346193, Kim 2022 PMID: 35853923, Ma 2023 PMID: 36597107). It has also been identified in 0.027% (12/44898) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). This variant has also been reported in ClinVar (Variation ID 869466). This variant is a deletion of 1 amino acid at position 3417 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PM4_Supporting.
Comment:
In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25792667, 29482514, 31581539, 31827275, 30896630, 35346193, 34265623, 35853923, 35982127, 36597107, 35939872, 34974475, 32802042, 38297847, 34325055, 38056549, 38860500)
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. |
Comment:
A heterozygous in-frame deletion variant was identified in exon 64 of MYO15A, NM_016239.3(MYO15A):c.10250_10252delCCT.This deletionresults in the lossof a serineat codon position 3417, NP_057323.3(MYO15A):p.(Ser3417del). The serine at this position has very high conservation (100 vertebrates, UCSC). It is situated in the FERM domain. This variant is present in the gnomAD population database at a frequency of 0.002%. It has not been previously observed in other clinical cases. Based on current information and in association with the NM_016239.3(MYO15A):c.9371dupA deletion variant, this variant has been classified as LIKELY PATHOGENIC.Parental testingindicates the variants are in trans. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness 3.NB: This variant has been reclassified from Class 3A (VUS with high clinical significance)to Class 4 (likely pathogenic).
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). This variant leads to inframe deletion located in a nonrepeat region that it is predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000869466 / PMID: 25792667). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant, c.10250_10252del, results in the deletion of 1 amino acid(s) of the MYO15A protein (p.Ser3417del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760069953, gnomAD 0.04%). This variant has been observed in individual(s) with deafness (PMID: 25792667, 29482514, 30896630, 34265623, 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. This variant is also known as c.10249_10251delTCC (p.F3417del) or c.10245_10247delCTC. ClinVar contains an entry for this variant (Variation ID: 869466). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Ser3417del variant in MYO15A has been reported in >15 compound heterozygous or homozygous individuals with hearing loss and segregated with disease in at least 4 affected individuals from 3 families (Miyagawa 2015 PMID: 25792667, Chang 2018 PMID: 29482514, Sun 2019 PMID: 30896630, Xu 2020 PMID: 32802042, Downie 2020 PMID: 31827275, Liang 2021 PMID: 34265623, Chen 2022 PMID: 34974475, Fu 2022 PMID: 35346193, Kim 2022 PMID: 35853923, Ma 2023 PMID: 36597107). It has also been identified in 0.027% (12/44898) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). This variant has also been reported in ClinVar (Variation ID 869466). This variant is a deletion of 1 amino acid at position 3417 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PM4_Supporting.
Comment:
In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25792667, 29482514, 31581539, 31827275, 30896630, 35346193, 34265623, 35853923, 35982127, 36597107, 35939872, 34974475, 32802042, 38297847, 34325055, 38056549, 38860500)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic screening of a Chinese cohort of children with hearing loss using a next-generation sequencing panel. | Ma J | Human genomics | 2023 | PMID: 36597107 |
| Full etiologic spectrum of pediatric severe to profound hearing loss of consecutive 119 cases. | Kim YS | Scientific reports | 2022 | PMID: 35853923 |
| Analysis of the genotype-phenotype correlation of MYO15A variants in Chinese non-syndromic hearing loss patients. | Fu Y | BMC medical genomics | 2022 | PMID: 35346193 |
| Hearing Features and Cochlear Implantation Outcomes in Patients With Pathogenic MYO15A Variants: a Multicenter Observational Study. | Chen PY | Ear and hearing | 2022 | PMID: 34974475 |
| Whole exome sequencing of six Chinese families with hereditary non-syndromic hearing loss. | Liang P | International journal of pediatric otorhinolaryngology | 2021 | PMID: 34265623 |
| Compound Heterozygous Mutations in TMC1 and MYO15A Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss in Two Chinese Han Families. | Xu P | Neural plasticity | 2020 | PMID: 32802042 |
| Exome sequencing in infants with congenital hearing impairment: a population-based cohort study. | Downie L | European journal of human genetics : EJHG | 2020 | PMID: 31827275 |
| Panel-based NGS reveals disease-causing mutations in hearing loss patients using BGISEQ-500 platform. | Sun Y | Medicine | 2019 | PMID: 30896630 |
| Expansion of phenotypic spectrum of MYO15A pathogenic variants to include postlingual onset of progressive partial deafness. | Chang MY | BMC medical genetics | 2018 | PMID: 29482514 |
| Mutations in the MYO15A gene are a significant cause of nonsyndromic hearing loss: massively parallel DNA sequencing-based analysis. | Miyagawa M | The Annals of otology, rhinology, and laryngology | 2015 | PMID: 25792667 |
Text-mined citations for rs760069953 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 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.