rs111033178
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_000260.4(MYO7A):โc.3719G>Aโ(p.Arg1240Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000946 in 1,575,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1240W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.3719G>A | p.Arg1240Gln | missense_variant | 29/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.3719G>A | p.Arg1240Gln | missense_variant | 29/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152248Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000747 AC: 14AN: 187292Hom.: 0 AF XY: 0.000109 AC XY: 11AN XY: 100916
GnomAD4 exome AF: 0.0000998 AC: 142AN: 1422802Hom.: 0 Cov.: 32 AF XY: 0.0000923 AC XY: 65AN XY: 704020
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74374
ClinVar
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | MYO7A: PM3:Very Strong, PM2, PM5, PP1, PP3 - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | 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). 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) performed at Invitae 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 19, 2020 | 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) - |
Usher syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 31, 2019 | 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. - |
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
MYO7A-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 05, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 25, 2023 | 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. 2006. PubMed ID: 16679490; Bharadwaj. 2000. PubMed ID: 10930322; Bonnet. 2011. PubMed ID: 21569298; Colombo. 2021. PubMed ID: 33576794). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-76901153-G-A). This variant is interpreted as pathogenic. - |
Usher syndrome type 1 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tรผbingen | Apr 24, 2024 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 03, 2017 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2014 | - - |
Usher syndrome type 1B Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 04, 2022 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 15, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at