ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.12575G>A (p.Arg4192His) (rs199605265)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000675140 SCV000800729 uncertain significance Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-07-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000480057 SCV000331629 pathogenic not provided 2015-05-07 criteria provided, single submitter clinical testing
GeneDx RCV000480057 SCV000565653 likely pathogenic not provided 2017-02-23 criteria provided, single submitter clinical testing The R4192H variant has been reported previously in association with USH2A-related disorders (Ávila-Fernández et al., 2010; Le et al., 2012; Neveling et al., 2012). However, the variant has also been published as unlikely to be associated with disease (McGee et al., 2010; Glöckle et al., 2014). The variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R4192H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000152569 SCV000201820 uncertain significance not specified 2014-07-16 criteria provided, single submitter clinical testing The Arg4192His variant in USH2A has been reported in four individuals with autosomal recessive retinitis pigmentosa (McGee 2010, Avila-Fernandez 2010, Tucker 2013). Three of these individuals were homozygous or compound heterozygous, and one was only reported to be heterozygous for this variant but there was no information about a second variant. The Arg4192His variant has been identified in 0.023% (2/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs199605265). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The arginine (Arg) at position 4192 is not conserved in mammals or evolutionary distant species, including many species carrying a histidine (His) at this position, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that the Arg4192His variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the Arg4192His variant is uncertain, these data suggest that is more likely to be benign.
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000505125 SCV000926717 uncertain significance Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505125 SCV000598777 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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