Submissions for variant NM_206933.4(USH2A):c.5298+5G>A

gnomAD frequency: 0.00001  dbSNP: rs1176314553

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001341472	SCV001535349	pathogenic	not provided	2024-10-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 26 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has been observed in individual(s) with retinitis pigmentosa and/or Usher syndrome (internal data). 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: 1038199). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001830436	SCV002767627	likely pathogenic	Usher syndrome type 2A	2024-09-22	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 39 (MIM#613809), and Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported once each as a VUS and pathogenic (ClinVar), and has been observed in a compound heterozygous individual with Usher syndrome (PMID: 34948090). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated in this individual's affected sibling, however this is insufficient evidence for segregation (VCGS). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.1841-2A>G) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001341472	SCV005690117	uncertain significance	not provided	2024-08-07	criteria provided, single submitter	clinical testing	Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 34948090)
Natera, Inc.	RCV001830436	SCV002091571	uncertain significance	Usher syndrome type 2A	2021-03-25	no assertion criteria provided	clinical testing