Submissions for variant NM_206933.4(USH2A):c.9371+1G>C

gnomAD frequency: 0.00002  dbSNP: rs41308425

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041950	SCV000065646	pathogenic	Rare genetic deafness	2016-06-23	criteria provided, single submitter	clinical testing	The c.9371+1G>C variant in USH2A has been reported in 5 individuals with Usher s yndrome with 4 of these individuals being compound heterozygous with a second pa thogenic USH2A variant (Le Quesne Stabej 2012, Zein 2015, Lenassi 2015, LMM data ). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or a bsent protein. Loss of function of the USH2A gene is an established disease mech anism in autosomal recessive Usher syndrome. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive Usher syndrome b ased on the predicted impact of the variant.
Eurofins Ntd Llc (ga)	RCV000726813	SCV000703232	pathogenic	not provided	2016-11-30	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001002711	SCV001156383	pathogenic	Usher syndrome type 2A	2019-02-01	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376451	SCV001573592	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.9371+1G>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726813	SCV001579752	pathogenic	not provided	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 47 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs41308425, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with retinitis pigmentosa or Usher syndrome (PMID: 22135276, 24938718, 26377068). ClinVar contains an entry for this variant (Variation ID: 48624). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000726813	SCV001804845	pathogenic	not provided	2020-04-20	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32176120, 25425308, 25649381, 26377068, 22135276, 24938718)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001002711	SCV002766704	pathogenic	Usher syndrome type 2A	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, 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) and retinitis pigmentosa (RP; MIM# 6138093). Null variants are associated with Usher syndrome while homozygous missense which lead to partially functional proteins typically causes non-syndromic RP (PMID: 20301515). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 4 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in individuals with Usher syndrome type 2 or retinitis pigmentosa (ClinVar; Deafness Variation Database; PMIDs: 22135276, 25472526). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV001376451	SCV004172039	pathogenic	Retinitis pigmentosa 39	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001002711	SCV004172040	pathogenic	Usher syndrome type 2A	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376451	SCV004208277	pathogenic	Retinitis pigmentosa 39	2024-03-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000726813	SCV005198970	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767034	SCV005381028	pathogenic	Usher syndrome	2024-08-15	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.9371+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of USH2A function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251224 control chromosomes. c.9371+1G>C has been reported in the literature in multiple individuals affected with Usher Syndrome or nonsyndromic retinitis pigmentosa (example, Le Quesne Stabej_2012, Reurink_2023, Xu_2014). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22135276, 36785559, 26377068, 24938718). ClinVar contains an entry for this variant (Variation ID: 48624). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005016326	SCV005645059	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-06-11	criteria provided, single submitter	clinical testing