ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.1036A>C (p.Asn346His) (rs369522997)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000710349 SCV000840547 pathogenic Usher syndrome 2018-09-14 reviewed by expert panel curation The allele frequency of the p.Asn346His variant in the USH2A gene is 0.016% (20/126318) of European (Non-Finnish) 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 Usher syndrome (PM2_Supporting). The p.Asn346His variant in USH2A has been reported to segregate with hearing loss in at least 7 families including 13 family members (PP1_S; 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 15241801, 24160897, 22135276, 26969326). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). Computational prediction tools and conservation analysis suggest that the p.Asn346His variant may impact the protein (PP3). 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: PM2_Supporting, PP1_S, PM3_VS, PP4, PP3.
Counsyl RCV000041668 SCV000487470 likely pathogenic Usher syndrome, type 2A 2016-08-18 criteria provided, single submitter clinical testing
Counsyl RCV000411779 SCV000487471 likely pathogenic Retinitis pigmentosa 39 2016-08-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727128 SCV000706010 pathogenic not provided 2017-03-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824797 SCV000065364 likely pathogenic Rare genetic deafness 2012-07-26 criteria provided, single submitter clinical testing The Asn346His variant in USH2A has been reported in 10 individuals with type II Usher syndrome (Weston 2000, Baux 2007, Dreyer 2000, Ouyang 2004, Pennings 2004, Vastinsalo 2012). 3/10 of these individuals were compound heterozygous. The As n residue at position 346 is highly conserved. This variant has been identified in 0.01% (1/8600) of European American chromosomes from a broad population by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although t his variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant i s likely pathogenic, though additional studies are required to fully establish i ts clinical significance.

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