The Ala230Val variant in MYO7A has been reported in a large Italian pedigree aff ected with nonsyndromic post-lingual progressive hearing loss showing autosomal dominant inheritance(Di Leva 2006). The variant co-segregated with hearing loss in several affected family members, and was not identified in unaffected family members or in 200 ethnically matched control chromosomes (Di Leva 2006). In addi tion, this variant was not identified in large population studies. Furthermore, the alanine (Ala) residue at position 230 is located in the conserved motor doma in of the MYO7A protein. Missense variants in this region of the protein have be en associated with autosomal dominant hearing loss. In summary, this variant mee ts our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) b ased upon segregation analysis.
ClinVar Genomic variation as it relates to human health
NM_000260.4(MYO7A):c.689C>T (p.Ala230Val)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000260.4(MYO7A):c.689C>T (p.Ala230Val)
Variation ID: 178993 Accession: VCV000178993.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.5 11: 77156958 (GRCh38) [ NCBI UCSC ] 11: 76868004 (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 Jan 31, 2015 Feb 14, 2024 Nov 27, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000260.4:c.689C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000251.3:p.Ala230Val missense NM_001127180.2:c.689C>T NP_001120652.1:p.Ala230Val missense NM_001369365.1:c.656C>T NP_001356294.1:p.Ala219Val missense NC_000011.10:g.77156958C>T NC_000011.9:g.76868004C>T NG_009086.2:g.33713C>T LRG_1420:g.33713C>T LRG_1420t1:c.689C>T LRG_1420p1:p.Ala230Val - Protein change
- A230V, A219V
- Other names
- -
- Canonical SPDI
- NC_000011.10:77156957:C:T
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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.
- -
- 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. |
|||
| MYO7A | - | - |
GRCh38 GRCh37 |
4340 | 4351 | |
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 (1) |
criteria provided, single submitter
|
Jun 11, 2013 | RCV000155771.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 12, 2016 | RCV000506187.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Feb 16, 2016 | RCV000225087.2 | |
| Pathogenic (2) |
criteria provided, single submitter
|
- | RCV001254945.2 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 27, 2023 | RCV001850134.6 | |
|
MYO7A-related disorder
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 5, 2023 | RCV004528892.1 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Oct 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604428.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
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Pathogenic
(Jun 11, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Rare genetic deafness
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000205482.4
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Comment:
The Ala230Val variant in MYO7A has been reported in a large Italian pedigree aff ected with nonsyndromic post-lingual progressive hearing loss showing autosomal dominant inheritance(Di … (more)
The Ala230Val variant in MYO7A has been reported in a large Italian pedigree aff ected with nonsyndromic post-lingual progressive hearing loss showing autosomal dominant inheritance(Di Leva 2006). The variant co-segregated with hearing loss in several affected family members, and was not identified in unaffected family members or in 200 ethnically matched control chromosomes (Di Leva 2006). In addi tion, this variant was not identified in large population studies. Furthermore, the alanine (Ala) residue at position 230 is located in the conserved motor doma in of the MYO7A protein. Missense variants in this region of the protein have be en associated with autosomal dominant hearing loss. In summary, this variant mee ts our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) b ased upon segregation analysis. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002521962.2
First in ClinVar: Jun 05, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28802369, 16449806) (less)
|
|
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Likely pathogenic
(Jul 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
MYO7A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004105633.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MYO7A c.689C>T variant is predicted to result in the amino acid substitution p.Ala230Val. This variant was reported to segregate with disease in a large … (more)
The MYO7A c.689C>T variant is predicted to result in the amino acid substitution p.Ala230Val. This variant was reported to segregate with disease in a large family with autosomal dominant non-syndromic sensorineural hearing loss (Di Leva et al. 2006. PubMed ID: 16449806). This variant was also reported as de novo in an individual with moderate bilateral hearing loss (Kaneko et al. 2017. PubMed ID: 28802369). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)
|
|
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Pathogenic
(Nov 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002239418.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 230 of the MYO7A protein (p.Ala230Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 230 of the MYO7A protein (p.Ala230Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 16449806, 28802369). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178993). 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 MYO7A protein function. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Bilateral sensorineural hearing impairment
Affected status: yes
Allele origin:
germline
|
Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo
Accession: SCV001762978.1
First in ClinVar: Oct 21, 2021 Last updated: Oct 21, 2021 |
Comment:
pathogenic missense heterozygous variant was found to segregate with HL in six members of the same family
Observation 1:
Clinical Features:
Postlingual sensorineural hearing impairment (present) , Progressive sensorineural hearing impairment (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
Observation 2:
Clinical Features:
Postlingual sensorineural hearing impairment (present) , Progressive sensorineural hearing impairment (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
Observation 3:
Clinical Features:
Postlingual sensorineural hearing impairment (present) , Progressive sensorineural hearing impairment (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
Observation 4:
Clinical Features:
Postlingual sensorineural hearing impairment (present) , Progressive sensorineural hearing impairment (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
Observation 5:
Clinical Features:
Postlingual sensorineural hearing impairment (present) , Progressive sensorineural hearing impairment (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
Observation 6:
Clinical Features:
Postlingual sensorineural hearing impairment (present) , Progressive sensorineural hearing impairment (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
|
|
|
Likely pathogenic
(Jan 20, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Bilateral sensorineural hearing impairment
Affected status: yes
Allele origin:
maternal
|
New York Genome Center
Accession: SCV001431027.2
First in ClinVar: Sep 05, 2020 Last updated: Sep 05, 2020 |
Comment:
The p.Ala230Val missense variant has been reported to co-segregate with autosomal dominant non-syndromic progressive hearing loss in a large Italian family [PMID: 16449806]. The p.Ala230Val … (more)
The p.Ala230Val missense variant has been reported to co-segregate with autosomal dominant non-syndromic progressive hearing loss in a large Italian family [PMID: 16449806]. The p.Ala230Val variant has also been reported in an unrelated 5-year old boy affected with moderate bilateral hearing loss [PMID: 28802369]. The variant is absent from the gnomAD database indicating that it is an extremely rare allele in the general population. The p.Ala230Val variant is predicted deleterious by various in silico prediction tools. The affected alanine residue is evolutionarily conserved and is located within the functionally important motor domain of MYO7A molecule. Missense variants in this region of the protein have been associated with autosomal dominant hearing loss. Based on the available evidence, the p.Ala230Val missense variant in the MYO7A gene is assessed as likely pathogenic. (less)
Family history: yes
Segregation observed: yes
Secondary finding: no
Method: whole genome sequencing
|
|
|
Pathogenic
(Feb 16, 2016)
|
no assertion criteria provided
Method: research
|
Autosomal dominant nonsyndromic hearing loss 11
Affected status: yes
Allele origin:
germline
|
Laboratory of Prof. Karen Avraham, Tel Aviv University
Accession: SCV000281977.1
First in ClinVar: Jun 16, 2016 Last updated: Jun 16, 2016
Comment:
NSHL; dominant, DFNA11
|
Comment:
childhood onset, progressive HL, also myopia
|
Comment:
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28802369, 16449806)
Comment:
The MYO7A c.689C>T variant is predicted to result in the amino acid substitution p.Ala230Val. This variant was reported to segregate with disease in a large family with autosomal dominant non-syndromic sensorineural hearing loss (Di Leva et al. 2006. PubMed ID: 16449806). This variant was also reported as de novo in an individual with moderate bilateral hearing loss (Kaneko et al. 2017. PubMed ID: 28802369). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 230 of the MYO7A protein (p.Ala230Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 16449806, 28802369). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178993). 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 MYO7A protein function. For these reasons, this variant has been classified as Pathogenic.
Comment:
pathogenic missense heterozygous variant was found to segregate with HL in six members of the same family
Comment:
The p.Ala230Val missense variant has been reported to co-segregate with autosomal dominant non-syndromic progressive hearing loss in a large Italian family [PMID: 16449806]. The p.Ala230Val variant has also been reported in an unrelated 5-year old boy affected with moderate bilateral hearing loss [PMID: 28802369]. The variant is absent from the gnomAD database indicating that it is an extremely rare allele in the general population. The p.Ala230Val variant is predicted deleterious by various in silico prediction tools. The affected alanine residue is evolutionarily conserved and is located within the functionally important motor domain of MYO7A molecule. Missense variants in this region of the protein have been associated with autosomal dominant hearing loss. Based on the available evidence, the p.Ala230Val missense variant in the MYO7A gene is assessed as likely pathogenic.
Comment:
childhood onset, progressive HL, also myopia
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:
The Ala230Val variant in MYO7A has been reported in a large Italian pedigree aff ected with nonsyndromic post-lingual progressive hearing loss showing autosomal dominant inheritance(Di Leva 2006). The variant co-segregated with hearing loss in several affected family members, and was not identified in unaffected family members or in 200 ethnically matched control chromosomes (Di Leva 2006). In addi tion, this variant was not identified in large population studies. Furthermore, the alanine (Ala) residue at position 230 is located in the conserved motor doma in of the MYO7A protein. Missense variants in this region of the protein have be en associated with autosomal dominant hearing loss. In summary, this variant mee ts our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) b ased upon segregation analysis.
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28802369, 16449806)
Comment:
The MYO7A c.689C>T variant is predicted to result in the amino acid substitution p.Ala230Val. This variant was reported to segregate with disease in a large family with autosomal dominant non-syndromic sensorineural hearing loss (Di Leva et al. 2006. PubMed ID: 16449806). This variant was also reported as de novo in an individual with moderate bilateral hearing loss (Kaneko et al. 2017. PubMed ID: 28802369). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 230 of the MYO7A protein (p.Ala230Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 16449806, 28802369). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178993). 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 MYO7A protein function. For these reasons, this variant has been classified as Pathogenic.
Comment:
pathogenic missense heterozygous variant was found to segregate with HL in six members of the same family
Comment:
The p.Ala230Val missense variant has been reported to co-segregate with autosomal dominant non-syndromic progressive hearing loss in a large Italian family [PMID: 16449806]. The p.Ala230Val variant has also been reported in an unrelated 5-year old boy affected with moderate bilateral hearing loss [PMID: 28802369]. The variant is absent from the gnomAD database indicating that it is an extremely rare allele in the general population. The p.Ala230Val variant is predicted deleterious by various in silico prediction tools. The affected alanine residue is evolutionarily conserved and is located within the functionally important motor domain of MYO7A molecule. Missense variants in this region of the protein have been associated with autosomal dominant hearing loss. Based on the available evidence, the p.Ala230Val missense variant in the MYO7A gene is assessed as likely pathogenic.
Comment:
childhood onset, progressive HL, also myopia
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic etiology of non-syndromic hearing loss in Latin America. | Lezirovitz K | Human genetics | 2022 | PMID: 34652575 |
| The first sporadic case of DFNA11 identified by next-generation sequencing. | Kaneko Y | International journal of pediatric otorhinolaryngology | 2017 | PMID: 28802369 |
| Identification of a novel mutation in the myosin VIIA motor domain in a family with autosomal dominant hearing loss (DFNA11). | Di Leva F | Audiology & neuro-otology | 2006 | PMID: 16449806 |
Text-mined citations for rs797044512 ...
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 Nov 25, 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.