Submissions for variant NM_206933.4(USH2A):c.9424G>T (p.Gly3142Ter) (rs397518048)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare 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
Invitae	RCV001055909	SCV001220324	pathogenic	not provided	2019-12-12	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. This variant is present in population databases (rs397518048, ExAC 0.006%). This variant has been observed to segregate with inherited retinal degeneration in a family (PMID: 28130426). In addition, this variant has been observed in several individuals affected with Usher syndrome (PMID: 17405132, 28653555, 23591405). ClinVar contains an entry for this variant (Variation ID: 48626). ClinVar contains an entry for this variant (Variation ID: 48626). Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). 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 Praxis fuer Humangenetik Tuebingen	RCV001055909	SCV001246990	pathogenic	not provided	2018-12-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001055909	SCV001446933	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Sharon lab,Hadassah-Hebrew University Medical Center	RCV001003263	SCV001161346	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research