ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.5581G>A (p.Gly1861Ser) (rs375668376)

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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 RCV000710326 SCV000840514 pathogenic Usher syndrome 2018-09-14 reviewed by expert panel curation The allele frequency of the p.Gly1861Ser variant in USH2A is 0.017% (3/17184) of East Asian chromosomes by the Genome Aggregation Database (, 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_P). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). This variant has been detected in 4 patients with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3_S; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). The variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID: 26310143). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). Computational prediction tools and conservation analysis suggest that the p.Gly1861Ser 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: PS4, PM2_P, PP3, PM3_S, PP1, PP4.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041861 SCV000065557 likely pathogenic Rare genetic deafness 2011-12-07 criteria provided, single submitter clinical testing The Gly1861Ser variant in USH2A has been identified by our laboratory in one pat ient with Usher syndrome who was a compound heterozygote with a pathogenic USH2A variant (c.8559-2A>G). Therefore, this variant is likely pathogenic.
Counsyl RCV000667951 SCV000792480 likely pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-06-26 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074044 SCV001239612 pathogenic Retinal dystrophy 2018-11-13 criteria provided, single submitter clinical testing
Invitae RCV001214945 SCV001386654 pathogenic not provided 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1861 of the USH2A protein (p.Gly1861Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs375668376, ExAC 0.01%). This variant has been observed in individual(s) with Usher syndrome (PMID: 23737954, 26310143, 26338283, 25356976, 29625443). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48535). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C5. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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. 5

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