ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.6431A>C (p.Glu2144Ala) (rs754703964)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756890 SCV000884858 uncertain significance not provided 2017-10-20 criteria provided, single submitter clinical testing The p.Glu2144Ala variant (rs754703964) has not been reported in the medical literature or previously identified in our laboratory, but it is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.039% in the Latino population (identified in 13 out of 33,484 chromosomes). The glutamic acid at codon 2144 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict that this variant does not affect the structure/function of the USH2A protein (SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). However, based on the available information, the clinical significance of the p.Glu2144Ala variant cannot be determined with certainty.
Invitae RCV000756890 SCV001412108 uncertain significance not provided 2019-08-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 2144 of the USH2A protein (p.Glu2144Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs754703964, ExAC 0.05%). This variant has not been reported in the literature in individuals with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 609375). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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