ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.14219C>A (p.Ala4740Asp) (rs539192853)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001252667 SCV001428426 uncertain significance Usher syndrome 2020-06-24 reviewed by expert panel curation The c.14219C>A (p.Ala4740Asp) variant in USH2A is present in 0.01085% (7/64542) of non-Finnish European chromosomes in gnomAD v3, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel (PM2_Supporting; gnomad.broadinstitute.org). This variant has been reported in one individual with Usher syndrome, who carried another rare missense VUS and phase was unknown (PM3 and PP4 not met; PMID: 22952768). This variant has also been observed in several probands with retinitis pigmentosa, including in two cases in compound heterozygosity with a frameshift variant or multi-exon deletion in USH2A (PM3; PMID: 23591405, 25649381, 28559085, 30718709). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (PP3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3, PM2_Supporting.
GeneDx RCV000492984 SCV000581721 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing The A4740D variant in the USH2A gene has been reported previously in an individual with Usher syndrome who also had the G1555C variant in the USH2A gene, however, parental studies were not performed to determine the phase of these variants (Licastro et al., 2012). The A4740D variant was also reported in an individual with retinitis pigmentosa who had A4740D in cis with L2301S as well as a nonsense variant in trans in the USH2A gene (Glockle et al., 2013). The A4740D variant is observed in 10/126,468 (0.0079%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The A4740D 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret A4740D as a variant of uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000492984 SCV000780322 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073605 SCV001239156 pathogenic Retinal dystrophy 2019-07-12 criteria provided, single submitter clinical testing
Invitae RCV000492984 SCV001418529 likely pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 4740 of the USH2A protein (p.Ala4740Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs539192853, ExAC 0.007%). This variant has been observed in individuals affected with Usher syndrome or retinal disease (PMID: 22952768, 28559085, 25649381, 30718709). ClinVar contains an entry for this variant (Variation ID: 429215). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Broad Institute Rare Disease Group, Broad Institute RCV000787725 SCV001950396 likely pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The p.Ala4740Asp variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PP1, PM2, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787725 SCV000926725 uncertain significance Retinitis pigmentosa 2018-04-01 no assertion criteria provided research

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