rs111033283
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000260.4(MYO7A):c.640G>A(p.Gly214Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,900 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 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.640G>A | p.Gly214Arg | missense_variant | 7/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.640G>A | p.Gly214Arg | missense_variant | 7/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.640G>A | p.Gly214Arg | missense_variant | 7/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.607G>A | p.Gly203Arg | missense_variant | 8/50 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249172Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135190
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461682Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727124
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 214 of the MYO7A protein (p.Gly214Arg). This variant is present in population databases (rs111033283, gnomAD 0.006%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 9382091, 16470552, 20497194, 24199935, 26969326). 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: 43327). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 21, 2014 | - - |
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 13, 2017 | - - |
Usher syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | research | SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation | Dec 31, 2022 | - - |
Usher syndrome type 1B Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 27, 2020 | - - |
Usher syndrome type 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
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 | Jul 29, 2021 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 23, 2016 | The p.Gly214Arg variant in MYO7A has been reported in over 10 probands with Ushe r syndrome who were either homozygous for the variant or compound heterozygous w ith a second pathogenic or likely pathogenic variant in MYO7A (Adato 1997, Apari si 2013, Bujakowska 2014, Jaijo 2011, Jaijo 2009, Jaijo 2006, Le Quesne Stabej 2 012, Riazuddin 2008, Roux 2011, LMM data). It has not been identified in large p opulation studies. Computational prediction tools and conservation analyses sugg est that this variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic for Usher syndrome in an autosomal rece ssive manner based on its presence in homozygosity or compound heterozygosity wi th a second pathogenic allele in many individuals with Usher syndrome, and low f requency in the general population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at