ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.5039A>G (p.Lys1680Arg) (rs150982499)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000710329 SCV000840519 uncertain significance Usher syndrome 2018-09-28 reviewed by expert panel curation The c.5039A>G (p.Lys1680Arg) variant in USH2A has been observed in the heterozygous state in one individual with hearing loss (PS4 not met; Partners LMM ClinVar SCV000201911.4). The allele frequency of the p.Lys1680Arg variant is 0.05% (20/34286) of Latino 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_P). In summary, this variant meets criteria to be classified as a variant of uncertain clinical significance for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000152611 SCV000201911 uncertain significance not specified 2017-08-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Lys1680Arg va riant in USH2A has been previously reported by our laboratory in the heterozygou s state in 1 individual with hearing loss, but a variant affecting the remaining copy of the gene has not been identified. This variant has been identified in 2 0/34268 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org/; dbSNP rs150982499). Although this variant has been see n in the general population, its frequency is not high enough to rule out a path ogenic role. Computational prediction tools and conservation analyses suggest th at this variant may not impact the protein, though this information is not predi ctive enough to rule out pathogenicity. In summary, while the clinical significa nce of the p.Lys1680Arg variant is uncertain, available data suggest that it is more likely to be benign.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724507 SCV000228276 uncertain significance not provided 2015-01-22 criteria provided, single submitter clinical testing
GeneDx RCV000724507 SCV000619904 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing The K1680R variant in the USH2A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The K1680R variant is observed in 6/11426 (0.05%) alleles from individuals of Latino background, in the ExAC dataset (Lek et al., 2016). The K1680R variant 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 conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K1680R as a variant of uncertain significance.

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