ClinVar Genomic variation as it relates to human health
NM_000260.4(MYO7A):c.3862G>C (p.Ala1288Pro)
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_000260.4(MYO7A):c.3862G>C (p.Ala1288Pro)
Variation ID: 866837 Accession: VCV000866837.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.5 11: 77190808 (GRCh38) [ NCBI UCSC ] 11: 76901853 (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 18, 2020 Feb 14, 2024 Dec 21, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000260.4:c.3862G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000251.3:p.Ala1288Pro missense NM_001127180.2:c.3862G>C NP_001120652.1:p.Ala1288Pro missense NM_001369365.1:c.3829G>C NP_001356294.1:p.Ala1277Pro missense NC_000011.10:g.77190808G>C NC_000011.9:g.76901853G>C NG_009086.2:g.67563G>C LRG_1420:g.67563G>C LRG_1420t1:c.3862G>C LRG_1420p1:p.Ala1288Pro - Protein change
- A1277P, A1288P
- Other names
- NM_000260.4(MYO7A):c.3862G>C
- p.Ala1288Pro
- Canonical SPDI
- NC_000011.10:77190807:G:C
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
- Links
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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MYO7A | - | - |
GRCh38 GRCh37 |
4273 | 4284 |
Conditions - Germline
Condition
Help
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
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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Oct 19, 2018 | RCV001075168.2 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 24, 2023 | RCV001339495.10 | |
Likely pathogenic (1) |
reviewed by expert panel
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Dec 21, 2022 | RCV003117740.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 19, 2023 | RCV003227909.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 18, 2023 | RCV003387963.1 |
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
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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
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
(Dec 21, 2022)
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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: SCV003800587.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
The NM_000260.4:c.3862G>C variant in the MYO7A gene is a missense variant predicted to cause substitution of alanine to proline at amino acid 1288 (p.Ala1288Pro). The … (more)
The NM_000260.4:c.3862G>C variant in the MYO7A gene is a missense variant predicted to cause substitution of alanine to proline at amino acid 1288 (p.Ala1288Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (7/110006 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.833, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in five individuals with hearing loss or clinical features of Usher syndrome who were compound heterozygous for the variant and a pathogenic or likely pathogenic variant. However, for each individual phase was unknown (PMID: 10094549, 26969326, SCV001533246.2, 2.5 PM3 points) (PM3_Strong, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PM3_Strong, PM2_Supporting, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022) (less)
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Likely pathogenic
(Oct 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001240780.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Likely pathogenic
(Jun 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762131.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Rod-cone dystrophy (present) , Hearing impairment (present)
Sex: male
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Likely pathogenic
(Apr 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 1
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003925604.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
This variant was identified as compound heterozygous with NM_000260.4:c.2766_2779del._x000D_ Criteria applied: PM3_STR, PM2_SUP, PP3, PP4
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Pathogenic
(Sep 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004099937.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: MYO7A c.3862G>C (p.Ala1288Pro) results in a non-conservative amino acid change located in the FERM domain (IPR000299) and Band 4.1 domain (IPR019749) of the … (more)
Variant summary: MYO7A c.3862G>C (p.Ala1288Pro) results in a non-conservative amino acid change located in the FERM domain (IPR000299) and Band 4.1 domain (IPR019749) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 212778 control chromosomes (i.e., 6 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3862G>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Usher Syndrome (e.g., Janecke_1999, Bharadwaj_2000, Jacobsen_2008, Krawitz_2014, Sloan-Heggen_2016, Zazo-Seco_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10930322, 18463160, 10094549, 25333064, 26969326, 28000701). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Dec 17, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002017875.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 24, 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: SCV001533246.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1288 of the MYO7A protein (p.Ala1288Pro). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1288 of the MYO7A protein (p.Ala1288Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Usher syndrome (PMID: 10094549, 10930322, 26969326; Invitae). ClinVar contains an entry for this variant (Variation ID: 866837). 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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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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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 |
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome. | Krawitz PM | Molecular genetics & genomic medicine | 2014 | PMID: 25333064 |
Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. | Jacobson SG | Human molecular genetics | 2008 | PMID: 18463160 |
Evaluation of the myosin VIIA gene and visual function in patients with Usher syndrome type I. | Bharadwaj AK | Experimental eye research | 2000 | PMID: 10930322 |
Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity. | Janecke AR | Human mutation | 1999 | PMID: 10094549 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/647cd6e5-0b17-415f-9309-9955f27e6ce8 | - | - | - | - |
Text-mined citations for rs749747871 ...
HelpRecord last updated May 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.