chr1-216175368-C-CT
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PVS1PP4PM3_Strong
This summary comes from the ClinGen Evidence Repository: The c.4510dupA (p.Arg1504LysX26) variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 21/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in 2 patients with hearing loss in trans with 2 different pathogenic variants (PM3_S; PMID:22135276). The allele frequency of the p.Arg1504LysX26 variant in the USH2A gene is 0.003% (3/111138) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). At least one patient with a variant in this gene displayed features of retinitis pigmentosa (PP4; PMID:22135276). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_S, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA273289/MONDO:0019501/005
Frequency
Consequence
NM_206933.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.4510_4511insA | p.Arg1504LysfsTer26 | frameshift_variant | 21/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.4510_4511insA | p.Arg1504LysfsTer26 | frameshift_variant | 21/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.4510_4511insA | p.Arg1504LysfsTer26 | frameshift_variant | 21/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.4510_4511insA | p.Arg1504LysfsTer26 | frameshift_variant | 21/21 | 1 | |||
USH2A | ENST00000674083.1 | c.4510_4511insA | p.Arg1504LysfsTer26 | frameshift_variant | 21/73 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250670Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135462
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461552Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727072
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74278
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | This sequence change creates a premature translational stop signal (p.Arg1504Lysfs*26) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs727503731, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 10729113, 15325563, 22135276). ClinVar contains an entry for this variant (Variation ID: 166504). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2022 | Observed with a pathogenic variant in an unrelated patient in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Carss et al., 2017); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel (ClinVar SCV000840511.3; Oza et al., 2018); This variant is associated with the following publications: (PMID: 22135276, 10729113, 15325563, 18641288, 28041643, 31980526, 32581362, 32037395) - |
Retinitis pigmentosa 39 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 16, 2017 | - - |
Usher syndrome type 2A Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 16, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Retinitis pigmentosa Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The p.Arg1504LysfsTer26 variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP3, PP4. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Usher syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Sep 10, 2018 | The c.4510dupA (p.Arg1504LysX26) variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 21/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in 2 patients with hearing loss in trans with 2 different pathogenic variants (PM3_S; PMID:22135276). The allele frequency of the p.Arg1504LysX26 variant in the USH2A gene is 0.003% (3/111138) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). At least one patient with a variant in this gene displayed features of retinitis pigmentosa (PP4; PMID: 22135276). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_S, PM2, PP4. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 16, 2021 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 10, 2013 | The Arg1504fs variant in USH2A has been reported in five individuals with Usher syndrome, of which at least three were compound heterozygous with a second patho genic USH2A variant (Weston 2000, Le Quesne Stabej 2012, Seyedahmadi 2004). This frameshift variant is predicted to alter the protein?s amino acid sequence begi nning at position 1504 and lead to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent p rotein. In summary, this variant meets our criteria to be classified as pathogen ic (http://pcpgm.partners.org/LMM). - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 27, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at