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

dbSNP: rs483353055

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001089677	SCV001245161	pathogenic	Usher syndrome	2023-09-26	reviewed by expert panel	curation	The c.3407G>A variant in USH2A is a missense variant predicted to cause substitution of serine to asparagine at amino acid 1136. This variant is absent from large population studies (PM2_Supporting, gnomAD v2.1.1). The computational predictor REVEL gives a score of 0.466 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been reported in at least 6 probands with USH2A-related disorders, including four individuals with autosomal recessive Usher syndrome and two individuals with isolated retinopathy. Of these individuals, the variant was confirmed in trans with a pathogenic variant in two individuals, but phase with a second pathogenic variant was unclear in the remaining 4 individuals (PM3_VeryStrong; PMID: 22135276, 25991456, 27957503, 36011334). Of note, the two individuals with isolated retinopathy harbored the pathogenic p.Cys759Phe variant, which is commonly found in individuals with an isolated retinopathy phenotype (SCV001334331.1). At least one patient with this variant was diagnosed with Usher syndrome (PP4). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive USH2A-related disorders including Usher syndrome and isolated retinopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PM3_VeryStrong, PP4. (The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2022)
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001231408	SCV001403928	pathogenic	not provided	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1136 of the USH2A protein (p.Ser1136Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Usher syndrome, retinitis pigmentosa, or cone-rod dystrophy (PMID: 22135276, 25991456, 27460420, 27957503, 28512305, 30718709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 133312). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000119824	SCV002768818	pathogenic	Usher syndrome type 2A	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated fibronectin type-III 1 domain (PDB). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. A missense variant (p.Ser1136Arg) of greater Grantham score has been reported as both a VUS and likely pathogenic, and was identified in a patient with congenital hearing loss, and their affected sibling (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic in multiple patients with Usher syndrome, inherited retinal disease and retinitis pigmentosa (ClinVar, PMID: 30718709,PMID: 28512305, PMID: 27208204, PMID: 25991456, PMID: 27957503, PMID: 27460420). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant was reported in two members of family with Usher syndrome, with unknown relation (PMID: 27957503). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787729	SCV000926732	likely pathogenic	Cone-rod dystrophy	2018-04-01	no assertion criteria provided	research