rs142898216
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_206933.4(USH2A):c.2332G>T(p.Asp778Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,902 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). Synonymous variant affecting the same amino acid position (i.e. D778D) has been classified as Likely benign.
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.2332G>T | p.Asp778Tyr | missense_variant | 13/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.2332G>T | p.Asp778Tyr | missense_variant | 13/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.2332G>T | p.Asp778Tyr | missense_variant | 13/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.2332G>T | p.Asp778Tyr | missense_variant | 13/21 | 1 | |||
USH2A | ENST00000674083.1 | c.2332G>T | p.Asp778Tyr | missense_variant | 13/73 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 250894Hom.: 1 AF XY: 0.0000295 AC XY: 4AN XY: 135554
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461788Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727202
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74304
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 13, 2021 | The USH2A c.2332G>T; p.Asp778Tyr variant (rs142898216; ClinVar Variation ID: 178583) has been previously observed in patients with clinical features of Usher syndrome (US) or retinitis pigmentosa (RP). One patient with US found to be homozygous for this variant, while one US and one RP patient were found to carry this variant in a presumed transheterozygous configuration with other established pathogenic variants in USH2A (Aller 2006, Lenassi 2015, Sloan-Heggen 2016). This variants is rare in the general population, though it is found at higher frequencies is African Americans in in the Genome Aggregation Database (0.056% MAF; 14 out of 24,968 chromosomes, including 1 homozygous individual). The aspartic acid at codon 778 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.598). Based on the available information, the clinical significance of this variant is uncertain. References: Aller et al. Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. J Med Genet. 2006 Nov;43(11):e55. PMID: 17085681 Lenassi et al. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. Eur J Hum Genet. 2015 Oct;23(10):1318-27. PMID: 25649381 Sloan-Heggen et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016 Apr;135(4):441-450. PMID: 26969326 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 778 of the USH2A protein (p.Asp778Tyr). This variant is present in population databases (rs142898216, gnomAD 0.05%). This missense change has been observed in individual(s) with Usher syndrome or non-syndromic retinal disease (PMID: 17085681, 25649381, 26969326; 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: 178583). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31904091, 31736247, 17085681, 26969326, 32637036, 25649381) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2017 | - - |
Usher syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2021 | Variant summary: USH2A c.2332G>T (p.Asp778Tyr) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) 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 5.2e-05 in 250894 control chromosomes in the gnomAD database, including 1 homozygote. c.2332G>T has been reported in the literature in multiple compound heterozygous individuals affected with Usher Syndrome or retinal disease (examples: Aller_2006, Sloan-Heggen_2016, Zenteno_2019, and McGowan_2020), as well as a homozygous individual with normal hearing and nyctalopia (Lenassi_2015). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and as a variant of uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 26, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 07, 2014 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp778Tyr variant in USH2A has been reported in 1 Spanish individual with Usher syndrome who also carried a known pathogenic variant (Aller 2006). This variant has been identified in 0.05% (2/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs142898216); howev er this frequency is not high enough to rule out a pathogenic role. Computationa l prediction tools suggest that the p.Asp778Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical signi ficance of the p.Asp778Tyr variant is uncertain. - |
Usher syndrome type 2A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 03, 2021 | NM_206933.2(USH2A):c.2332G>T(D778Y) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. D778Y has been observed in cases with relevant disease (PMID: 31736247, 25649381, 17085681, 26969326). Functional assessments of this variant are not available in the literature. D778Y has been observed in population frequency databases (gnomAD: AFR 0.05%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.2332G>T(D778Y) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at