ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.3407G>A (p.Ser1136Asn) (rs483353055)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001089677 SCV001245161 likely pathogenic Usher syndrome 2020-01-21 reviewed by expert panel curation The p.Ser1136Asn variant in USH2A is absent from gnomAD v2.1.1 (PM2). This variant has been detected in 4 probands with Usher syndrome. For 2 of those probands, a pathogenic or suspected-pathogenic variant was observed in trans, and in 2 the variant was observed in trans with a rare missense variant (PM3_Strong; PMID:22135276, 25991456, 27460420, 28512305). At least one patient with this variant displayed features of Usher syndrome type 2, which is highly specific for USH2A (PP4; PMID: 22135276, 25991456). Of note, this variant has been observed in several other probands presenting with retinitis pigmentosa without hearing loss. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM3_Strong, PM2, PP4).
Molecular Genetics Laboratory; Baylor College of Medicine RCV000119824 SCV000154750 unknown Usher syndrome, type 2A criteria provided, single submitter not provided Converted during submission to Uncertain significance.
Counsyl RCV000675179 SCV000800808 likely pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2018-04-18 criteria provided, single submitter clinical testing
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000119824 SCV001156368 pathogenic Usher syndrome, type 2A 2019-02-01 criteria provided, single submitter clinical testing
Invitae RCV001231408 SCV001403928 pathogenic not provided 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1136 of the USH2A protein (p.Ser1136Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Usher syndrome, retinitis pigmentosa, or cone-rod dystrophy (PMID: 22135276, 28512305, 27957503, 27460420, 30718709, 25991456). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 133312). 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). This variant disrupts the p.Ser1136 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787729 SCV000926732 likely pathogenic Cone-rod dystrophy 2018-04-01 no assertion criteria provided research

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