Submissions for variant NM_206933.4(USH2A):c.9424G>T (p.Gly3142Ter)

dbSNP: rs397518048

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041952	SCV000065648	pathogenic	Usher syndrome; Rare genetic deafness	2018-07-20	criteria provided, single submitter	clinical testing	The p.Gly3142X variant has been reported in 9 individuals with Usher syndrome, 4 patients with retinal dystrophy, and 1 patient with sensorineural hearing loss, and at least 10 of these individuals were compound heterozygous for a second pa thogenic USH2A variant (Baux 2007, Sandberg 2008, McGee 2010, Glockle 2013, Kraw itz 2014, Baux 2014, Lenarduzzi 2015, Lenassi 2015, Bonnet 2016, LMM data). This variant was identified in 0.005% (5/110538) of European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org); however, thi s frequency is low enough to be consistent with a recessive carrier frequency. T his nonsense variant leads to a premature termination codon at position 3142, wh ich is predicted to lead to a truncated or absent protein. In summary, this vari ant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the predicted impact of the variant, the reported compound het erozygous individuals with Usher syndrome, and its low frequency in the general population. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PM2, PP4.
Ambry Genetics	RCV000624783	SCV000740836	pathogenic	Inborn genetic diseases	2015-03-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055909	SCV001220324	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly3142*) 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 (rs397518048, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with Usher syndrome and inherited retinal degeneration (PMID: 17405132, 23591405, 28130426, 28653555). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48626). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074810	SCV001240408	pathogenic	Retinal dystrophy	2019-07-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001055909	SCV001246990	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	USH2A: PM3:Very Strong, PVS1, PM2
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001055909	SCV001446933	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723630	SCV001950406	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Gly3142Ter 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. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Fulgent Genetics, Fulgent Genetics	RCV002504928	SCV002816438	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2021-10-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003387741	SCV004182692	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001831709	SCV004182693	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003387741	SCV004207713	pathogenic	Retinitis pigmentosa 39	2023-10-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492342	SCV004241515	pathogenic	Usher syndrome	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.9424G>T (p.Gly3142X) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 250190 control chromosomes (gnomAD). c.9424G>T has been reported in the literature as a biallelic genotype in individuals affected with Usher Syndrome (e.g. Neuhaus_2017). These data indicate that the variant is very likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 28944237). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001831709	SCV005051992	pathogenic	Usher syndrome type 2A	2024-02-01	criteria provided, single submitter	curation
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003263	SCV001161346	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001831709	SCV002088403	pathogenic	Usher syndrome type 2A	2020-07-10	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003387741	SCV004099464	pathogenic	Retinitis pigmentosa 39	2023-10-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732599	SCV005346871	pathogenic	USH2A-related disorder	2024-09-10	no assertion criteria provided	clinical testing	The USH2A c.9424G>T variant is predicted to result in premature protein termination (p.Gly3142*). This variant has been reported with other USH2A loss-of-function variants in multiple individuals with Usher syndrome (see for example, Baux et al. 2007. PubMed ID: 17405132; Magliulo et al. 2017. PubMed ID: 28653555; Table S5, Colombo et al. 2021. PubMed ID: 33576794). This variant is reported in 0.0053% of alleles in individuals of European (non-Finnish) descent in gnomAD. Nonsense variants in USH2A are expected to be pathogenic. This variant is interpreted as pathogenic.