Submissions for variant NM_206933.4(USH2A):c.11241C>A (p.Tyr3747Ter)

gnomAD frequency: 0.00003  dbSNP: rs777465132

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000710334	SCV000840528	pathogenic	Usher syndrome	2018-09-17	reviewed by expert panel	curation	The p.Tyr3747X variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 58/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). The allele frequency of the p.Tyr3747X variant in the Ush2A gene is 0.017% (4/24020) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss ( PM2_Supporting). This variant has been detected in 1 patient with hearing loss in trans with a suspected pathogenic variant (PM3_Supporting, Partners LMM internal data SCV000713838.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied: PVS1, PM2_Supporting, PM3_Supporting.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000605356	SCV000713838	pathogenic	Rare genetic deafness	2018-01-30	criteria provided, single submitter	clinical testing	The p.Tyr3747X variant in USH2A has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 0.02% (4/24020) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs777465132). This nonsense variant leads to a premat ure termination codon at position 3747, which is predicted to lead to a truncate d or absent protein. Variants in USH2A resulting in a loss of function of the pr otein is an established disease mechanism in autosomal recessive Usher syndrome. In addition, this variant is likely in trans with the deletion of exons 63-64 i n USH2A given that previous cases with the deletion did not carry this variant. This provides additional evidence that the variant is pathogenic. In summary, th is variant meets our criteria to be classified as pathogenic for autosomal reces sive Usher syndrome. ACMG/AMP Criteria applied: PVS1; PM2; PM3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057761	SCV001222271	pathogenic	not provided	2024-06-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr3747*) 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 (rs777465132, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with inherited retinal dystrophy (PMID: 30337596). ClinVar contains an entry for this variant (Variation ID: 506273). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001057761	SCV001803549	pathogenic	not provided	2023-07-21	criteria provided, single submitter	clinical testing	Nonsense 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; Reported as pathogenic by the ClinGen Hearing Loss Expert Panel (Oza et al., 2018); This variant is associated with the following publications: (PMID: 30311386, 30337596, 34948090)
Baylor Genetics	RCV003471974	SCV004200711	pathogenic	Retinitis pigmentosa 39	2023-05-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001271137	SCV001451990	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing