ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.1966G>A (p.Asp656Asn) (rs146824138)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658550 SCV000780326 likely pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000627016 SCV000747719 uncertain significance Joubert syndrome; Congenital cerebellar hypoplasia; Motor delay; Delayed speech and language development; Amblyopia; Hypoplasia of the brainstem; Congenital sensorineural hearing impairment; Cerebellar hemisphere hypoplasia 2017-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000658550 SCV000515232 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing The D656N variant in the USH2A gene has been reported previously in an individual with Usher syndrome, although it is unknown if this individual also harbored a second variant on the other USH2A allele (Cremers et al., 2007). While not present in the homozygous state, the D656N variant is observed in 81/66702 (0.12%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The D656N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D656N as a variant of uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041804 SCV000065500 uncertain significance not specified 2016-06-30 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Asp656Asn var iant in USH2A has been reported in 2 individuals with Usher syndrome and 1 indiv idual with hearing loss (Cremers 2007, LMM data). However, in 1 of the individu als with Usher syndrome, two pathogenic variants in a different gene were identi fied that explained disease and in the remaining individuals, a pathogenic varia nt on the remaining copy of USH2A was not identified. This variant has been ide ntified in 0.1% (81/66702) of European chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs146824138). Although this variant has been seen in the general population, its frequency is not high enoug h to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Asp656Asn variant is uncer tain, these data suggest that it is more likely to be benign.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505164 SCV000598794 uncertain significance Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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