rs140487302
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_206933.4(USH2A):c.6590C>T(p.Thr2197Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00044 in 1,613,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2197A) has been classified as Uncertain significance.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.6590C>T | p.Thr2197Ile | missense_variant | 34/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.6590C>T | p.Thr2197Ile | missense_variant | 34/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.6590C>T | p.Thr2197Ile | missense_variant | 34/73 |
Frequencies
GnomAD3 genomes ? AF: 0.000322 AC: 49AN: 152020Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000291 AC: 73AN: 250856Hom.: 0 AF XY: 0.000273 AC XY: 37AN XY: 135580
GnomAD4 exome AF: 0.000452 AC: 660AN: 1461074Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 303AN XY: 726856
GnomAD4 genome ? AF: 0.000322 AC: 49AN: 152020Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19AN XY: 74264
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 19, 2022 | Identified in a patient with Usher syndrome who also harbored several other variants in the USH2A gene (phase unknown) in published literature (Carss et al., 2017); 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: 32707200, 30190494, 28041643, 35128159, Hu2022[abstract]) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 03, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Thr2197Ile vari ant in USH2A has not been reported in individuals with hearing loss, but has bee n identified in 0.07% (6/8600) of European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs140487302). Al though this variant has been seen in the general population, its frequency is no t high enough to rule out a pathogenic role. Computational analyses (biochemica l amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of this variant cannot be determined with certainty; however based upon the frequency data described above, we would lean towards a more lik ely benign role. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 02, 2022 | Variant summary: USH2A c.6590C>T (p.Thr2197Ile) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 250856 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00029 vs 0.011), allowing no conclusion about variant significance. c.6590C>T has been reported in the literature as a non-informative genotype (second allele not specified, or multiple alleles with/without phase specified) in individuals undergoing analysis for inherited retinal diseases (example, Carss_2017. Gonzalez-del Pozo_2018, Li_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. At-least one co-occurrence in cis with another pathogenic variant(s) have been reported (Gonzalez-del Pozo_2018, USH2A c.6590C>T, p.Cys520*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 06, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 09, 2022 | - - |
Usher syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Usher syndrome type 2A Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at