ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.12574C>T (p.Arg4192Cys) (rs750396156)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001089679 SCV001245163 uncertain significance Usher syndrome 2020-01-21 reviewed by expert panel curation The c.12574C>T (p.Arg4192Cys) variant in USH2A is present in 0.007055% (9/127578) of non-Finnish European chromosomes in gnomAD v2 (PM2_Supporting). This variant was observed in at least 3 probands with Usher syndrome, including one individual with a suspected pathogenic missense variant in trans and another with a suspected pathogenic nonsense variant with phase unknown (PMID: 24516651, 27460420). At least one of these patients was clinically evaluated and confirmed to have both sensorineural deafness and retinitis pigmentosa, which are highly specific for Usher syndrome (PP4; PMID: 27460420). However, a third proband harbored this variant in cis with the known pathogenic p.Cys759Phe variant (BP2; PMID: 29912909). Of note, this variant has been observed in several other probands presenting with retinitis pigmentosa without hearing loss. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel: BP2, PM2_P, PM3, PP4.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000498898 SCV000332810 uncertain significance not provided 2015-07-10 criteria provided, single submitter clinical testing
GeneDx RCV000498898 SCV000589528 pathogenic not provided 2018-11-05 criteria provided, single submitter clinical testing The R4192C variant in the USH2A gene has been reported previously in association with autosomal recessive Usher syndrome type 2 and in association with autosomal recessive retinitis pigmentosa when present in the homozygous state or when in trans with another disease-causing USH2A variant (Corton et al., 2013; Coppieters et al., 2014; Bonnet et al., 2016; Carss et al., 2017; Perez-Carro et al., 2018). The R4192C variant is observed in 9/125,058 (0.0072%) alleles from individuals of non-Finnish Eurpean background in large population cohorts (Lek et al., 2016). The R4192C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R4192C as a pathogenic variant.
Counsyl RCV000675149 SCV000800749 likely pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-02-15 criteria provided, single submitter clinical testing
Invitae RCV000498898 SCV001207227 pathogenic not provided 2020-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 4192 of the USH2A protein (p.Arg4192Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs750396156, ExAC 0.005%). This variant has been observed in individuals affected with autosomal recessive retinitis pigmentosa (arRP) and also segregated with arRP in a family (PMID: 29912909, 27157150, 23940504). ClinVar contains an entry for this variant (Variation ID: 281818). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075586 SCV001241213 pathogenic Retinal dystrophy 2019-01-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000498898 SCV001246244 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504963 SCV000598776 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000678644 SCV000804733 likely pathogenic Retinitis pigmentosa 39 2016-09-01 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000504963 SCV000926913 likely pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research

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