rs876657655
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000260.4(MYO7A):c.6062A>G(p.Lys2021Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,426,868 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. K2021K) has been classified as Benign.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.6062A>G | p.Lys2021Arg | missense_variant | 45/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.6062A>G | p.Lys2021Arg | missense_variant | 45/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000140 AC: 2AN: 1426868Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2AN XY: 705974
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Usher syndrome type 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Jan 18, 2023 | The c.6062A>G (NM_000260.4(MYO7A):c.6062A>G (p.Lys2021Arg)) variant in MYO7A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 2021. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.748, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least 4 individuals with Usher Syndrome type 1 (from three families). For one of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant (phase unknown) ((NM_000260.4(MYO7A):c.722G>A (p.Arg241His); 0.5 PM3 points; 21436283). In another family, this variant was found in the homozygous state in a male adolescent, 14 years of age, with bilateral congenital hearing loss and features of night blindness (0.5 PM3 points; Allan, 2014; 1). Due to consanguinity, 2 individuals from the same family were homozygous for the variant (0.25 PM3 points; Allam, 2014; 1) (PM3). At least one patient with this disease displayed sensorineural hearing loss and retinitis pigmentosa, which is highly specific for Usher Syndrome 1 (PMID: 21436283; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_supporting, PP3, PM3, PP4; Version 2; 2022). 1. https://docs.google.com/document/d/17VJ_cidV8dqRQMHTzSVrFa-7PrmJ4trkw2wQsNEPqvk/edit - |
Usher syndrome type 1B Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 05, 2015 | The p.Lys2021Arg variant in MYO7A has been reported in one individual with type I Usher syndrome who was compound heterozygous for a second likely pathogenic va riant in MYO7A (Roux 2011). This variant was absent from large population studie s. Computational prediction tools and conservation analyses suggest that the p.L ys2021Arg variant may impact the protein. In summary, although additional studie s are required to fully establish its clinical significance, this variant is lik ely pathogenic based on the previous report in an individual with Usher syndrome . - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 18, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 09, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); 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: 21436283) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at