ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.14369A>C (p.Gln4790Pro)

gnomAD frequency: 0.00004  dbSNP: rs149807281
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV001073804 SCV001239366 uncertain significance Retinal dystrophy 2018-04-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001245666 SCV001418968 likely pathogenic not provided 2025-01-13 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 4790 of the USH2A protein (p.Gln4790Pro). This variant is present in population databases (rs149807281, gnomAD 0.002%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 34906470; internal data). ClinVar contains an entry for this variant (Variation ID: 866070). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. 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.
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376409 SCV001573537 uncertain significance Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.14369A>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
GeneDx RCV001245666 SCV002031142 uncertain significance not provided 2021-11-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002557899 SCV003572447 uncertain significance Inborn genetic diseases 2021-07-20 criteria provided, single submitter clinical testing The c.14369A>C (p.Q4790P) alteration is located in exon 66 (coding exon 65) of the USH2A gene. This alteration results from a A to C substitution at nucleotide position 14369, causing the glutamine (Q) at amino acid position 4790 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004587040 SCV005076156 uncertain significance not specified 2024-04-29 criteria provided, single submitter clinical testing Variant summary: USH2A c.14369A>C (p.Gln4790Pro) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251268 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.14369A>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 866070). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001828535 SCV002088225 uncertain significance Usher syndrome type 2A 2020-09-21 no assertion criteria provided clinical testing

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