rs770553471
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_206933.4(USH2A):c.14426C>T(p.Thr4809Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,098 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.14426C>T | p.Thr4809Ile | missense_variant | 66/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.14426C>T | p.Thr4809Ile | missense_variant | 66/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.14426C>T | p.Thr4809Ile | missense_variant | 66/73 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251388Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135870
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727248
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 19, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 4809 of the USH2A protein (p.Thr4809Ile). This variant is present in population databases (rs770553471, gnomAD 0.007%). This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 18665195, 21569298, 24944099, 25649381, 27460420; Invitae). 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: 438016). 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 USH2A 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 | Dec 07, 2018 | The T4809I variant in the USH2A gene has been reported previously in individuals with Usher syndrome type II who also harbored an additional variant in the USH2A gene, although parental studies were not performed to confirm the phase of these variants in all of these studies (Ebermann et al., 2009; Bonnet et al., 2011; Baux et al., 2014; Lenassi et al., 2015; Bonnet et al., 2016; Carss et al., 2017). The T4809I variant is observed in 1/15,304 (0.0065%) alleles from individuals of African background and 2/246,160 global alleles in large population cohorts (Lek et al., 2016). The T4809I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret T4809I as a likely pathogenic variant. - |
Usher syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2024 | Variant summary: USH2A c.14426C>T (p.Thr4809Ile) results in a non-conservative amino acid change in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251388 control chromosomes. c.14426C>T has been reported in the literature in at-least four individuals affected with Usher Syndrome, in whom, this variant was at a compound heterozygous state along with a different second pathogenic variant (Bonnet_2016, 2011, Toms_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27460420, 21569298, 31998945). ClinVar contains an entry for this variant (Variation ID: 438016). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 10, 2018 | - - |
Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at