rs111033215
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000260.4(MYO7A):c.5648G>A(p.Arg1883Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1883W) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.5648G>A | p.Arg1883Gln | missense_variant | 41/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.5648G>A | p.Arg1883Gln | missense_variant | 41/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000326 AC: 8AN: 245768Hom.: 0 AF XY: 0.0000300 AC XY: 4AN XY: 133456
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1460026Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 726130
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74414
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2018 | The R1883Q missense variant in the MYO7A gene has been reported previously in association with Usher syndrome type IB, and has been reported in trans with a pathogenic variant on the opposite allele (in trans) in multiple individuals (Ouyang et al., 2005; Nakanishi et al., 2010; Bonnet et al., 2011; Le Quesne Stabej et al., 2012). The R1883Q variant is observed in 3/34194 (0.009%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The R1883Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We classify this variant as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1883 of the MYO7A protein (p.Arg1883Gln). This variant is present in population databases (rs111033215, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 20844544, 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: 43294). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Usher syndrome type 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Refractive Surgery Department, Bright Eye Hospital | May 13, 2022 | WES identified two novel compound heterozygous mutations (c.5648G>A(rs111033215) and c.6238-1G>C) in MYO7A in two patients with Usher syndrome type 1. We found that the mutation c.5648G>A was predicted as “Probably Damaging” by the PolyPhen2 analysis. It was also evaluated as “Deleterious” and “Disease Causing” by other prediction programs (SIFT, PROVEIN, MutationTaster). Thus, the mutation of c.5648G>A was potentially pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 16, 2018 | - - |
Usher syndrome type 1B Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 26, 2018 | The p.Arg1883Gln variant in MYO7A has been reported in 4 individuals with Usher Syndrome Type I (USH1), all of whom also carried a second pathogenic variant (Ou yang 2005, Nakanishi 2010, Bonnet 2011, Le Quesne Stabej 2012, Jacobson 2011). T he p.Arg1883Gln variant has been identified in 0.0088% (3/34194) Latino chromoso mes and 0.004% (10/274046) of total chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033215). Although this variant has been seen in the general population, its overall frequency is low en ough to be consistent with a recessive carrier frequency. Computational predicti on tools and conservation analysis suggest that the p.Arg1883Gln variant may imp act the protein. In summary, this variant meets criteria to be classified as pat hogenic for autosomal recessive Usher syndrome based upon multiple occurrences a s a compound heterozygous variant with pathogenic variants in the same gene in i ndividuals with Usher syndrome, low frequency in the gnomAD database, and predic ted impact on protein. ACMG/AMP criteria applied: PM3_Very Strong, PM2_Supportin g, PP3, PP4. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at