The MYO7A c.3719G>A (p.Arg1240Gln) missense variant has been reported in at least 11 studies in which it is found in 26 individuals with Usher syndrome type 1 including five homozygotes, 18 compound heterozygotes, two heterozygotes, and in one individual in a double heterozygous state with a variant in the USH2A gene (Janecke et al. 1999; Bharadwaj et al. 2000; Pennings et al. 2004; Gerber et al. 2006; Pennings et al. 2006; Roux et al. 2006; Jaijo et al. 2007; Jacobsen et al. 2008; Jaijo et al. 2010; Bonnet et al. 2011; Le Quesne Stabej et al. 2012). While this variant has not been reported in conjunction with nonsyndromic hearing loss, disease risk cannot be ruled out. The variant was not found in at least 1075 healthy controls (Janecke et al. 1999; Roux et al. 2006; Jaijo et al. 2010; Bonnet et al. 2011) and is reported at a frequency of 0.000723 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the combined evidence, the p.Arg1240Gln variant is classified as pathogenic for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000260.4(MYO7A):c.3719G>A (p.Arg1240Gln)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
10 out of 18 submissions contributed to this 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.
18
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000260.4(MYO7A):c.3719G>A (p.Arg1240Gln)
Variation ID: 43218 Accession: VCV000043218.61
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.5 11: 77190108 (GRCh38) [ NCBI UCSC ] 11: 76901153 (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 29, 2016 Mar 22, 2025 Jan 13, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000260.4:c.3719G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000251.3:p.Arg1240Gln missense NM_001127180.2:c.3719G>A NP_001120652.1:p.Arg1240Gln missense NM_001369365.1:c.3686G>A NP_001356294.1:p.Arg1229Gln missense NC_000011.10:g.77190108G>A NC_000011.9:g.76901153G>A NG_009086.2:g.66863G>A LRG_1420:g.66863G>A LRG_1420t1:c.3719G>A LRG_1420p1:p.Arg1240Gln Q13402:p.Arg1240Gln - Protein change
- R1240Q, R1229Q
- Other names
- -
- Canonical SPDI
- NC_000011.10:77190107:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
Exome Aggregation Consortium (ExAC) 0.00043
- 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 |
4655 | 4667 | |
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 (2) |
criteria provided, single submitter
|
Apr 24, 2024 | RCV000036122.16 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 13, 2025 | RCV000256123.46 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jul 31, 2019 | RCV000504703.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 7, 2014 | RCV000623302.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jan 3, 2017 | RCV000984006.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2023 | RCV001075882.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 27, 2024 | RCV000763279.12 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001272514.9 | |
|
MYO7A-related disorder
|
Pathogenic (2) |
criteria provided, single submitter
|
Oct 5, 2018 | RCV004528176.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 05, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
MYO7A-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914542.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The MYO7A c.3719G>A (p.Arg1240Gln) missense variant has been reported in at least 11 studies in which it is found in 26 individuals with Usher syndrome … (more)
The MYO7A c.3719G>A (p.Arg1240Gln) missense variant has been reported in at least 11 studies in which it is found in 26 individuals with Usher syndrome type 1 including five homozygotes, 18 compound heterozygotes, two heterozygotes, and in one individual in a double heterozygous state with a variant in the USH2A gene (Janecke et al. 1999; Bharadwaj et al. 2000; Pennings et al. 2004; Gerber et al. 2006; Pennings et al. 2006; Roux et al. 2006; Jaijo et al. 2007; Jacobsen et al. 2008; Jaijo et al. 2010; Bonnet et al. 2011; Le Quesne Stabej et al. 2012). While this variant has not been reported in conjunction with nonsyndromic hearing loss, disease risk cannot be ruled out. The variant was not found in at least 1075 healthy controls (Janecke et al. 1999; Roux et al. 2006; Jaijo et al. 2010; Bonnet et al. 2011) and is reported at a frequency of 0.000723 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the combined evidence, the p.Arg1240Gln variant is classified as pathogenic for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Aug 15, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001241523.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Pathogenic
(Jul 31, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059774.7
First in ClinVar: May 03, 2013 Last updated: Jul 06, 2020 |
Comment:
The Arg1240Gln variant in MYO7A has been reported in at least 14 probands with Usher syndrome (Jacobson 2008, Bharadwaj 2000, Gerber 2006, Jaijo 2007, Jaijo … (more)
The Arg1240Gln variant in MYO7A has been reported in at least 14 probands with Usher syndrome (Jacobson 2008, Bharadwaj 2000, Gerber 2006, Jaijo 2007, Jaijo 2009, Janecke 1999, Pennings 2006, Pennings 2004, Roux 2006). Eleven of these probands were homozygous or compound heterozygous. It has also segregated in at least one affected sibling as observed by testing in our laboratory, and it has been reported in ClinVar (Variation ID 43218). This variant has been identified in 0.01% (12/80298) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive allele frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PP1_Supporting, PP4. (less)
Number of individuals with the variant: 13
|
|
|
Pathogenic
(Jan 13, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000955876.7
First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1240 of the MYO7A protein (p.Arg1240Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1240 of the MYO7A protein (p.Arg1240Gln). This variant is present in population databases (rs111033178, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10930322, 15043528, 16652077, 17361009, 18463160, 20513143, 21569298, 21873662, 22135276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43218). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1240 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 24199935), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 01, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608608.33
First in ClinVar: Oct 30, 2017 Last updated: Mar 22, 2025 |
Comment:
MYO7A: PM3:Very Strong, PM2, PM5, PP1, PP3
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Sep 07, 2014)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741118.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Congenital sensorineural hearing impairment (present) , Retinal dystrophy (present) , Optic atrophy (present) , Seizures (present) , Global developmental delay (present)
Sex: female
Ethnicity/Population group: Hispanic
|
|
|
Pathogenic
(Jun 19, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321919.8
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 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: 18463160, 16679490, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18463160, 16679490, 20513143, 21436283, 19683999, 25468891, 16652077, 16400615, 17361009, 27068579, 28559085, 10094549, 10930322, 15043528, 21569298, 16963483, 26969326, 22135276, 15221449, 9354784, 28041643, 31479088, 31980526, 32581362, 31589614, 32467589, 33576794, 33576163, 10612833) (less)
|
|
|
Pathogenic
(Apr 24, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV005013287.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Clinical Features:
Hearing impairment (present) , Rod-cone dystrophy (present) , Cone-rod dystrophy (present)
|
|
|
Pathogenic
(Jan 01, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV005068477.1
First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024 |
|
|
|
Pathogenic
(Jan 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome type 1
Autosomal recessive nonsyndromic hearing loss 2 Autosomal dominant nonsyndromic hearing loss 11
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893923.3
First in ClinVar: Mar 31, 2019 Last updated: Jan 25, 2025 |
|
|
|
Pathogenic
(Jan 03, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000788911.2
First in ClinVar: Aug 05, 2018 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Sep 05, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
MYO7A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004119534.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The MYO7A c.3719G>A variant is predicted to result in the amino acid substitution p.Arg1240Gln. This variant has been reported to be causative for autosomal recessive … (more)
The MYO7A c.3719G>A variant is predicted to result in the amino acid substitution p.Arg1240Gln. This variant has been reported to be causative for autosomal recessive Usher syndrome (Roux et al. 2006. PubMed ID: 16679490; Bharadwaj et al. 2000. PubMed ID: 10930322; Bonnet et al. 2011. PubMed ID: 21569298; supplementary data, Colombo et al. 2021. PubMed ID: 33576794). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 01, 2015)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: research
|
Usher syndrome
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000599121.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
|
|
|
Pathogenic
(Sep 16, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Usher syndrome type 1B
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001454586.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001923520.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954855.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975636.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
Method: literature only
|
Usher syndrome type 1
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000268744.2
First in ClinVar: May 29, 2016 Last updated: Oct 01, 2022 |
|
|
| click to load more submissions click to collapse | |||||
Comment:
Comment:
The Arg1240Gln variant in MYO7A has been reported in at least 14 probands with Usher syndrome (Jacobson 2008, Bharadwaj 2000, Gerber 2006, Jaijo 2007, Jaijo 2009, Janecke 1999, Pennings 2006, Pennings 2004, Roux 2006). Eleven of these probands were homozygous or compound heterozygous. It has also segregated in at least one affected sibling as observed by testing in our laboratory, and it has been reported in ClinVar (Variation ID 43218). This variant has been identified in 0.01% (12/80298) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive allele frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PP1_Supporting, PP4.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1240 of the MYO7A protein (p.Arg1240Gln). This variant is present in population databases (rs111033178, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10930322, 15043528, 16652077, 17361009, 18463160, 20513143, 21569298, 21873662, 22135276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43218). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1240 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 24199935), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
MYO7A: PM3:Very Strong, PM2, PM5, PP1, PP3
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18463160, 16679490, 20513143, 21436283, 19683999, 25468891, 16652077, 16400615, 17361009, 27068579, 28559085, 10094549, 10930322, 15043528, 21569298, 16963483, 26969326, 22135276, 15221449, 9354784, 28041643, 31479088, 31980526, 32581362, 31589614, 32467589, 33576794, 33576163, 10612833)
Comment:
The MYO7A c.3719G>A variant is predicted to result in the amino acid substitution p.Arg1240Gln. This variant has been reported to be causative for autosomal recessive Usher syndrome (Roux et al. 2006. PubMed ID: 16679490; Bharadwaj et al. 2000. PubMed ID: 10930322; Bonnet et al. 2011. PubMed ID: 21569298; supplementary data, Colombo et al. 2021. PubMed ID: 33576794). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
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 MYO7A c.3719G>A (p.Arg1240Gln) missense variant has been reported in at least 11 studies in which it is found in 26 individuals with Usher syndrome type 1 including five homozygotes, 18 compound heterozygotes, two heterozygotes, and in one individual in a double heterozygous state with a variant in the USH2A gene (Janecke et al. 1999; Bharadwaj et al. 2000; Pennings et al. 2004; Gerber et al. 2006; Pennings et al. 2006; Roux et al. 2006; Jaijo et al. 2007; Jacobsen et al. 2008; Jaijo et al. 2010; Bonnet et al. 2011; Le Quesne Stabej et al. 2012). While this variant has not been reported in conjunction with nonsyndromic hearing loss, disease risk cannot be ruled out. The variant was not found in at least 1075 healthy controls (Janecke et al. 1999; Roux et al. 2006; Jaijo et al. 2010; Bonnet et al. 2011) and is reported at a frequency of 0.000723 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the combined evidence, the p.Arg1240Gln variant is classified as pathogenic for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The Arg1240Gln variant in MYO7A has been reported in at least 14 probands with Usher syndrome (Jacobson 2008, Bharadwaj 2000, Gerber 2006, Jaijo 2007, Jaijo 2009, Janecke 1999, Pennings 2006, Pennings 2004, Roux 2006). Eleven of these probands were homozygous or compound heterozygous. It has also segregated in at least one affected sibling as observed by testing in our laboratory, and it has been reported in ClinVar (Variation ID 43218). This variant has been identified in 0.01% (12/80298) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive allele frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PP1_Supporting, PP4.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1240 of the MYO7A protein (p.Arg1240Gln). This variant is present in population databases (rs111033178, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10930322, 15043528, 16652077, 17361009, 18463160, 20513143, 21569298, 21873662, 22135276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43218). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1240 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 24199935), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
MYO7A: PM3:Very Strong, PM2, PM5, PP1, PP3
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18463160, 16679490, 20513143, 21436283, 19683999, 25468891, 16652077, 16400615, 17361009, 27068579, 28559085, 10094549, 10930322, 15043528, 21569298, 16963483, 26969326, 22135276, 15221449, 9354784, 28041643, 31479088, 31980526, 32581362, 31589614, 32467589, 33576794, 33576163, 10612833)
Comment:
The MYO7A c.3719G>A variant is predicted to result in the amino acid substitution p.Arg1240Gln. This variant has been reported to be causative for autosomal recessive Usher syndrome (Roux et al. 2006. PubMed ID: 16679490; Bharadwaj et al. 2000. PubMed ID: 10930322; Bonnet et al. 2011. PubMed ID: 21569298; supplementary data, Colombo et al. 2021. PubMed ID: 33576794). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy. | Karali M | Scientific reports | 2022 | PMID: 36460718 |
| The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A. | Mansard L | International journal of molecular sciences | 2021 | PMID: 34948090 |
| Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families. | Mei X | Neural plasticity | 2021 | PMID: 33976695 |
| Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome. | Colombo L | Investigative ophthalmology & visual science | 2021 | PMID: 33576794 |
| Genotype-phenotype correlation in patients with Usher syndrome and pathogenic variants in MYO7A: implications for future clinical trials. | Galbis-Martínez L | Acta ophthalmologica | 2021 | PMID: 33576163 |
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period. | Weisschuh N | Human mutation | 2020 | PMID: 32531858 |
| Frequency of Usher gene mutations in non-syndromic hearing loss: higher variability of the Usher phenotype. | Cesca F | Journal of human genetics | 2020 | PMID: 32467589 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases. | Hanany M | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31964843 |
| PHENOTYPIC CHARACTERISTICS OF ROD-CONE DYSTROPHY ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT. | Khateb S | Retina (Philadelphia, Pa.) | 2020 | PMID: 31479088 |
| Usher Syndrome Type I. | Adam MP | - | 2020 | PMID: 20301442 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
| DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System. | Sommen M | Human mutation | 2016 | PMID: 27068579 |
| Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Natural history and retinal structure in patients with Usher syndrome type 1 owing to MYO7A mutation. | Lenassi E | Ophthalmology | 2014 | PMID: 24199935 |
| Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. | Le Quesne Stabej P | Journal of medical genetics | 2012 | PMID: 22135276 |
| Retinal disease course in Usher syndrome 1B due to MYO7A mutations. | Jacobson SG | Investigative ophthalmology & visual science | 2011 | PMID: 21873662 |
| Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. | Bonnet C | Orphanet journal of rare diseases | 2011 | PMID: 21569298 |
| Nasal epithelial cells are a reliable source to study splicing variants in Usher syndrome. | Vaché C | Human mutation | 2010 | PMID: 20513143 |
| Microarray-based mutation analysis of 183 Spanish families with Usher syndrome. | Jaijo T | Investigative ophthalmology & visual science | 2010 | PMID: 19683999 |
| UMD-USHbases: a comprehensive set of databases to record and analyse pathogenic mutations and unclassified variants in seven Usher syndrome causing genes. | Baux D | Human mutation | 2008 | PMID: 18484607 |
| Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. | Jacobson SG | Human molecular genetics | 2008 | PMID: 18463160 |
| MYO7A mutation screening in Usher syndrome type I patients from diverse origins. | Jaijo T | Journal of medical genetics | 2007 | PMID: 17361009 |
| Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%. | Roux AF | Journal of medical genetics | 2006 | PMID: 16679490 |
| Audiologic performance and benefit of cochlear implantation in Usher syndrome type I. | Pennings RJ | The Laryngoscope | 2006 | PMID: 16652077 |
| USH1A: chronicle of a slow death. | Gerber S | American journal of human genetics | 2006 | PMID: 16400615 |
| Evaluation of visual impairment in Usher syndrome 1b and Usher syndrome 2a. | Pennings RJ | Acta ophthalmologica Scandinavica | 2004 | PMID: 15043528 |
| Evaluation of the myosin VIIA gene and visual function in patients with Usher syndrome type I. | Bharadwaj AK | Experimental eye research | 2000 | PMID: 10930322 |
| Erratum: analysis of DNA elements that modulate myosin VIIa expression in humans. | Orten DJ | Human mutation | 2000 | PMID: 10612833 |
| Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity. | Janecke AR | Human mutation | 1999 | PMID: 10094549 |
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Text-mined citations for rs111033178 ...
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Record last updated Mar 22, 2025
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