rs111033284
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000409709.9(MYO7A):c.722G>A(p.Arg241His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. R241C) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000409709.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.722G>A | p.Arg241His | missense_variant | 7/49 | ENST00000409709.9 | NP_000251.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.722G>A | p.Arg241His | missense_variant | 7/49 | 1 | NM_000260.4 | ENSP00000386331 | ||
MYO7A | ENST00000458637.6 | c.722G>A | p.Arg241His | missense_variant | 7/49 | 1 | ENSP00000392185 | P1 | ||
MYO7A | ENST00000409619.6 | c.689G>A | p.Arg230His | missense_variant | 8/50 | 1 | ENSP00000386635 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248492Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134924
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1460962Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6AN XY: 726736
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152362Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74498
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 241 of the MYO7A protein (p.Arg241His). This variant is present in population databases (rs111033284, gnomAD 0.006%). This missense change has been observed in individuals with Usher syndrome or autosomal recessive non-syndromic sensorineural deafness (PMID: 21436283, 23770805, 26226137, 31479088). ClinVar contains an entry for this variant (Variation ID: 43340). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 2022 | Identified with a second MYO7A variant in siblings with retinitis pigmentosa in published literature; information regarding hearing status was not available (Khateb et al., 2020); 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: 10930322, 23770805, 26309859, 26338283, 16963483, 26226137, 30303587, 21436283, 31479088) - |
Usher syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 28, 2023 | Variant summary: MYO7A c.722G>A (p.Arg241His) results in a non-conservative amino acid change located in the myosin head, motor domain (IPR001609) 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 1.6e-05 in 248492 control chromosomes (gnomAD). c.722G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Usher Syndrome or autosomal recessive non-syndromic sensorineural deafness (examples: Roux_2011, Shahzad_2013, Bademci2016). 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: 23770805 , 26226137 , 21436283). Other variants affecting the same residue (p.Arg241Cys, p.Arg241Gly) have been classified pathogenic in ClinVar suggesting this residue may be critical for normal function of the protein (CV IDs 438180, 2137200). Three submitters have cited 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. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 02, 2015 | - - |
Hearing loss, autosomal recessive Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 22, 2007 | - - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at