Submissions for variant NM_206933.4(USH2A):c.5857+2T>C

gnomAD frequency: 0.00002  dbSNP: rs397518022

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001004785	SCV001164270	likely pathogenic	Usher syndrome	2019-10-29	reviewed by expert panel	curation	The c.5857+2T>C variant in USH2A has been identified in at least 3 probands with Usher syndrome, including two who were compound heterozygous for a second pathogenic variant though phase was not confirmed (PM3, PP4; PMID 20507924, 20507924, 18641288, LMM unpublished data SCV000065566.6). The allele frequency of this variant is 0.01% (2/15422) of European chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing, though the exact impact is unknown. Exon 29 is in-frame, and if the variant results in exon skipping, it would remove <10% of the USH2A protein. However, two truncating pathogenic / likely pathogenic variants in this exon have been reported in ClinVar, which may suggest it is required for normal protein function (PVS1_Moderate). 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 (PVS1_Moderate, PM3, PP4, PM2_Supporting).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041870	SCV000065566	pathogenic	Rare genetic deafness	2013-03-11	criteria provided, single submitter	clinical testing	The 5857+2T>C variant has been reported in 2 probands with the clinical features of Usher syndrome type II, one of whom carried a second pathogenic USH2A varian t (Sandberg 2008, McGee 2010). This variant occurs in the invariant region (+1/2 ) of the 5' splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our cr iteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Illumina Laboratory Services, Illumina	RCV000295857	SCV000354057	uncertain significance	USH2A-related disorder	2016-06-14	criteria provided, single submitter	clinical testing	The c.5857+2T>C variant variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been described in two studies in which it was found in a compound heterozygous state in one individual with autosomal recessive retinitis pigmentosa, and in a heterozygous state in two individuals with Usher syndrome type II (Sandberg et al. 2008; McGee et al. 2010). Control data are unavailable for this variant which is also not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of splice donor variants and the supporting evidence from the literature, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for USH2A-related disorders.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036145	SCV001199495	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 29 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 (rs397518022, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with autosomal recessive inherited retinal dystrophy and Usher syndrome, type 2A (PMID: 18641288, 20507924; Invitae). ClinVar contains an entry for this variant (Variation ID: 48544). 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.
Blueprint Genetics	RCV001074605	SCV001240196	pathogenic	Retinal dystrophy	2019-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001036145	SCV001825643	likely pathogenic	not provided	2023-01-12	criteria provided, single submitter	clinical testing	Identified in individuals with Usher syndrome type II in the published literature, however, it is unknown if a second USH2A variant was identified in some cases (Sandberg et al., 2008; McGee et al., 2010); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 20507924, 18641288, 35266249, 26582918)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002291270	SCV002583770	likely pathogenic	Usher syndrome type 2A	2022-07-25	criteria provided, single submitter	clinical testing	PVS1_Moderate, PM2, PM3, PP4
Baylor Genetics	RCV000675153	SCV004206327	pathogenic	Retinitis pigmentosa 39	2024-03-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000675153	SCV000800763	likely pathogenic	Retinitis pigmentosa 39	2017-05-09	no assertion criteria provided	clinical testing