rs780308389
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_206933.4(USH2A):c.1055C>T(p.Thr352Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,646 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. T352S) has been classified as Uncertain significance.
Frequency
Consequence
NM_206933.4 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 |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.1055C>T | p.Thr352Ile | missense_variant | 6/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.1055C>T | p.Thr352Ile | missense_variant | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.1055C>T | p.Thr352Ile | missense_variant | 6/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.1055C>T | p.Thr352Ile | missense_variant | 6/21 | 1 | |||
USH2A | ENST00000674083.1 | c.1055C>T | p.Thr352Ile | missense_variant | 6/73 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250992Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135630
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461646Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727114
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The USH2A c.1055C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1-S. Based on this evidence we have classified this variant as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 14, 2017 | - - |
Usher syndrome type 2A Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 26, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
USH2A-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | The c.1055C>T;p.(Thr352Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 438002; PMID: 29142287; 28653555; 27460420; 25575603; 24498627; 21569298; 18273898; 17405132) - PS4. The variant is present at low allele frequencies population databases (rs780308389 - gnomAD 0.00007968%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr352Ile) was detected in trans with a pathogenic variant (PMID: 29142287; 28653555; 25575603; 24498627; 17405132) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 29142287) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 16, 2024 | The USH2A c.1055C>T variant is predicted to result in the amino acid substitution p.Thr352Ile. This variant was reported in the compound heterozygous or homozygous states in individuals with retinitis pigmentosa or Usher syndrome (Magliulo et al. 2017. PubMed ID: 28653555; Table S4 & S5, Colombo et al. 2021. PubMed ID: 33576794; Colombo et al. 2021. PubMed ID: 34781295; Table S2, Mansard et al. 2021. PubMed ID: 34948090; Table S1, Karali et al. 2022. PubMed ID: 36460718). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is listed in ClinVar as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/438002/). This variant is interpreted as likely pathogenic. - |
Usher syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 352 of the USH2A protein (p.Thr352Ile). This variant is present in population databases (rs780308389, gnomAD 0.002%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 17405132, 24498627, 25575603, 28653555, 29142287). 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: 438002). 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. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 11, 2017 | The p.Thr352Ile variant in USH2A has been reported in at least 7 individuals wit h Usher syndrome, 5 of whom carried a second pathogenic variant on the other all ele (Baux 2007, Cremers 2007, Dreyer 2008, Bonnet 2011, Besnard 2013, Lenarduzzi 2015, Bonnet 2016). This variant has also been identified in 2/111896 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org; dbSNP rs780308389). This frequency in the general population is low en ough to be consistent with a recessive carrier frequency for Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosoma l recessive Usher syndrome based on multiple occurrences with a second pathogeni c variant in affected individuals. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 06, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at