ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.1966G>A (p.Asp656Asn) (rs146824138)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171539 SCV001334324 likely benign Usher syndrome 2020-05-25 reviewed by expert panel curation The allele frequency of the c.1966G>A (p.Asp656Asn) variant in USH2A is 0.095% (16/10466 CI 95%) of Finnish alleles in gnomAD v3., which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). The variant has been identified in 3 probands with hearing loss and 2 probands with Usher syndrome (SCV000065500.6; PMID: 16963483); however an alternate cause of hearing loss in other genes was identified in 3 probands (SCV000065500.6), and a second variant in USH2A was not identified in the other two probands (SCV000065500.6; PMID: 16963483). Finally, in the last proband, another likely benign variant was identified with phasing unknown (SCV000065500.6). Altogether, this evidence does not meet the criteria set to apply PM3_Supporting. Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, the c.1966G>A (p.Asp656Asn) variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041804 SCV000065500 uncertain significance not specified 2019-05-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Asp656Asn variant in USH2A has been reported in 3 individuals with Usher syndrome and 1 individual with hearing loss (Cremers 2007, LMM data). However, the role of this variant in these 3 individuals remains inconclusive for various reasons (2 of the individuals with Usher syndrome [LMM data] had two pathogenic variants in a different gene that explained disease, the study that reported 1 individual with Usher syndrome did not comment on whether or not a second variant was present [Cremers 2007], and the individual with hearing loss [LMM data], did not harbor a pathogenic variant on the remaining copy of USH2A). In addition, the p.Asp656Asn variant has been reported in 1 individual with inherited isolated retinitis pigmentosa along with 2 additional USH2A variants (p.Thr3667Pro and p.Gln3326X; Carss 2017); however, phase was undetermined. This variant has also been identified in 0.1% (140/126536) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 48481). 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 this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting.
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.
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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658550 SCV000780326 likely pathogenic not provided 2017-12-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075196 SCV001240809 uncertain significance Retinal dystrophy 2018-11-13 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001099033 SCV001255441 uncertain significance Usher syndrome, type 2A 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000505164 SCV001255442 uncertain significance Retinitis pigmentosa 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV000658550 SCV001413919 uncertain significance not provided 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 656 of the USH2A protein (p.Asp656Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs146824138, ExAC 0.1%). This variant has been observed in an individual with clinical features of retinitis pigmentosa along with a two different variants in the USH2A gene (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 48481). 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: "Benign"; Align-GVGD: "Class C15"). 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.
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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