Submissions for variant NM_206933.4(USH2A):c.2167+5G>A

gnomAD frequency: 0.00009  dbSNP: rs771583281

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667707	SCV000792201	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-06-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000667707	SCV000893290	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2021-08-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035076	SCV001198388	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 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 (rs771583281, gnomAD 0.01%). This variant has been observed in individuals with Usher syndrome 2 or retinitis pigmentosa (PMID: 12112664, 21151602, 24516651, 30190494). This variant is also known as IVS12+5G>A. ClinVar contains an entry for this variant (Variation ID: 552447). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20497194). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073540	SCV001239087	pathogenic	Retinal dystrophy	2019-05-22	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376264	SCV001573343	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.2167+5G>A 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, PM3. Based on this evidence we have classified this variant as Pathogenic.
GeneDx	RCV001035076	SCV001982672	pathogenic	not provided	2024-03-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20497194, 25525159, 12112664, 25366773, 30190494, 24944099, 24516651, 23647439, 31589614, 33576794, 31456290, 34948090, 34781295, 32188678, 21151602)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509496	SCV002819702	pathogenic	Usher syndrome	2022-12-20	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.2167+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site and one predicts an extreme weakening of this site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in both out-of frame skipping of exon 12 and an in-frame skipping of the exon with the use of an alternate splice site (Jaijo_2011). The variant allele was found at a frequency of 4e-05 in 250350 control chromosomes. This frequency is not higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (4e-05 vs 0.011), allowing no conclusion about variant significance. c.2167+5G>A has been reported in the literature in multiple individuals affected with Usher Syndrome or Retinitis Pigmentosa (Avila-Fernandez_2010, Gao_2021, Jaijo_2011, Najera_2002, Columbo_2021), and some of these patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 , and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV001376264	SCV004172185	likely pathogenic	Retinitis pigmentosa 39	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001829844	SCV004172186	likely pathogenic	Usher syndrome type 2A	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376264	SCV004208362	pathogenic	Retinitis pigmentosa 39	2024-03-12	criteria provided, single submitter	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003280	SCV001161363	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001829844	SCV002093962	pathogenic	Usher syndrome type 2A	2020-12-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732991	SCV005360167	pathogenic	USH2A-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The USH2A c.2167+5G>A variant is predicted to interfere with splicing. This variant has been reported as pathogenic in patients with Usher syndrome and inherited retinal dystrophies, with functional studies demonstrating it results in exon skipping (Najera et al. 2002. PubMed ID: 12112664; Jaijo et al. 2011. PubMed ID: 20497194; González-Del Pozo et al 2018. PubMed ID: 30190494). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.