Submissions for variant NM_206933.4(USH2A):c.12067-2A>G

gnomAD frequency: 0.00001  dbSNP: rs397517978

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000390593	SCV000065408	pathogenic	Rare genetic deafness	2013-05-13	criteria provided, single submitter	clinical testing	The 12067-2A>G variant in USH2A has been reported in five individuals with Usher syndrome type 2, one individual with autosomal recessive retinitis pigmentosa a nd one individual with congenital sensorineural hearing loss (Sandberg 2008, Aus lender 2008, Garcia-Garcia 2011, LMM unpublished data). Four of these probands w ere homozygous or compound heterozygous. Segregation of this variant with disea se was demonstrated in two affected family members (Auslender 2008). In addition , 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 ab sent protein. In summary, this variant meets our criteria to be classified as pa thogenic.
Eurofins Ntd Llc (ga)	RCV000412841	SCV000341017	pathogenic	not provided	2016-05-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000412841	SCV000490873	pathogenic	not provided	2023-10-19	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32531858, 34315337, 25525159, 25404053, 28981474, 26850479, 29490346, 30190494, 31456290, 34426522, 31589614, 32037395, 18641288, 22004887, 34948090, 34148116, 35266249, 36785559, 36819107, 36875754, 27460420, 36460718, 36979683, 37287646, 18452394)
Fulgent Genetics, Fulgent Genetics	RCV000666727	SCV000893284	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412841	SCV000933043	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 61 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 (rs397517978, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with Usher syndrome (PMID: 18452394, 22004887, 25404053, 28981474). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48390). 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	RCV001073917	SCV001239482	pathogenic	Retinal dystrophy	2018-06-19	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000983997	SCV001573489	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.12067-2A>G 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, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.
Revvity Omics, Revvity	RCV000412841	SCV002020850	pathogenic	not provided	2020-10-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001271128	SCV002060347	pathogenic	Usher syndrome type 2A	2021-10-01	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.12067-2A>G is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.12067-2A>G has been observed in cases with relevant disease (PMID: 27460420, 18452394, 22004887). Functional assessments of this variant are not available in the literature. c.12067-2A>G has been observed in population frequency databases (gnomAD: AMR 0.04%). In summary, NM_206933.2(USH2A):c.12067-2A>G is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000412841	SCV002062872	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
3billion	RCV001271128	SCV002572967	pathogenic	Usher syndrome type 2A	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000048390 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000983997	SCV004173919	pathogenic	Retinitis pigmentosa 39	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001271128	SCV004173921	pathogenic	Usher syndrome type 2A	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000983997	SCV004208172	pathogenic	Retinitis pigmentosa 39	2024-03-18	criteria provided, single submitter	clinical testing
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV001271128	SCV005073818	pathogenic	Usher syndrome type 2A	2024-06-10	criteria provided, single submitter	research	Pathogenic by Deafness Variation Database based and by ClinVar many entries
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003259	SCV001161341	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001271128	SCV001451979	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732590	SCV005348340	pathogenic	USH2A-related disorder	2024-08-20	no assertion criteria provided	clinical testing	The USH2A c.12067-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported many times as causative for Usher syndrome (see for examples: Auslender et al. 2008. PubMed ID: 18452394; Aparisi et al. 2014. PubMed ID: 25404053; González-Del Pozo. 2018. PubMed ID: 30190494). This variant is reported in 0.041% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice acceptor site in USH2A are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.