ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.12505A>G (p.Thr4169Ala) (rs113107803)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000787993 SCV000927021 likely benign Usher syndrome 2019-02-25 reviewed by expert panel curation The filtering allele frequency of the p.Thr4169Ala variant in the USH2A gene is 0.32% for African chromosomes by gnomAD (82/24940 with 95% CI) (BS1). Computational predictors for the variant suggest no impact on the gene or gene product (REVEL score: 0.207) (BP4). Of note, this variant was reported in 4 patients with Usher syndrome (PMID:28041643) though without any convincing evidence for pathogenicity (PM3 not met). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS1 and BP4
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000152570 SCV000201821 likely benign not specified 2017-04-25 criteria provided, single submitter clinical testing p.Thr4169Ala in exon 63 of USH2A: This variant is not expected to have clinical significance because it has been identified in 0.3% (80/24002) of African chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs113107803).
GeneDx RCV000727077 SCV000583079 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing The T4169A variant in the USH2A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, a missense variant at this same codon (T4169P) has been reported in combination with another USH2A variant in a patient with a clinical diagnosis of Usher syndrome (Baux et al., 2014), supporting the functional importance of this codon. The T4169A variant is observed in 24/10,264 (0.2%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The T4169A 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. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. T4169A is reported as likely benign in ClinVar by a different clinical laboratory (SCV000201821.3; Landrum et al., 2016). We interpret T4169A as a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727077 SCV000705415 uncertain significance not provided 2017-02-15 criteria provided, single submitter clinical testing
Counsyl RCV000669865 SCV000794658 uncertain significance Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-10-10 criteria provided, single submitter clinical testing
Invitae RCV000727077 SCV001039753 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000152570 SCV001157775 uncertain significance not specified 2018-08-21 criteria provided, single submitter clinical testing The USH2A c.12505A>G; p.Thr4169Ala (rs113107803), to our knowledge, is not reported in the medical literature or in gene-specific databases. The variant is reported in the ClinVar database (Variation ID: 166435) and variant is found in the African population with an overall allele frequency of 0.3% (80/24002 alleles) in the Genome Aggregation Database. The threonine at this position is weakly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Considering available information, the clinical significance of this variant cannot be determined with certainty. Pathogenic USH2A variants are causative for autosomal recessive Usher syndrome (MIM: 276901) or retinitis pigmentosa (MIM: 613809).
Blueprint Genetics RCV001075370 SCV001240991 uncertain significance Retinal dystrophy 2018-06-11 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505138 SCV000598774 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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