ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.5012G>A (p.Gly1671Asp) (rs727505116)

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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 RCV001004787 SCV001164272 uncertain significance Usher syndrome 2019-10-22 reviewed by expert panel curation The c.5012G>A (p.Gly1671Asp) variant in USH2A is present in 0.0392% (12/30616) of South Asian chromosomes in gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the Hearing Loss Variant Curation Expert Panel. Computational prediction tools and conservation analyses suggest that the p.Gly1671Asp variant may impact the protein (PP3). This variant was identified in 3 individuals with Usher syndrome harboring this variant; however, either variants in other alleles were not identified or alternate mechanisms of disease were present (LMM internal data, SCV000206290.5; PMID: 22135276). The p.Gly1671Asp variant was also found in four individuals with retinitis pigmentosa, but not Usher syndrome (PMID: 28041643, 26667666). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156571 SCV000206290 uncertain significance not specified 2014-08-08 criteria provided, single submitter clinical testing The Gly1671Asp variant in USH2A has been previously identified in two Indian ind ividuals with Usher syndrome (Le Quesne Stabej 2012, personal communication), th ough one individual did not carry a second USH2A variant and the second individu al carried two other USH2A variants and it was not clear which of the three vari ants was contributing to the disease. This variant has not been identified in la rge population databases; however, there is insufficient data to assess the freq uency of this variant in Indian control populations. Computational prediction t ools and conservation analyses suggest that the Gly1671Asp variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the Gly1671Asp variant is uncer tain.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725477 SCV000337203 uncertain significance not provided 2015-11-12 criteria provided, single submitter clinical testing
Invitae RCV000725477 SCV001207883 likely pathogenic not provided 2020-01-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 1671 of the USH2A protein (p.Gly1671Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs727505116, ExAC 0.04%). This variant has been observed in individual(s) with retinitis pigmentosa (PMID: 26667666, 28041643). ClinVar contains an entry for this variant (Variation ID: 179773). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505112 SCV000598814 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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