Submissions for variant NM_206933.4(USH2A):c.12067-2A>G (rs397517978)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare 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a nd one individual with congenital sensorineural hearing loss (Sandberg 2008, Aus lender 2008, Garcia-Garcia 2011, LMM unpublished data).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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000412841	SCV000341017	pathogenic	not provided	2016-05-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000412841	SCV000490873	pathogenic	not provided	2018-03-08	criteria provided, single submitter	clinical testing	The c.12067-2 A>G splice site variant has been previously reported in association with Usher syndrome (Auslender et al., 2008; Aparisi et al., 2014; Tekin et al., 2016). This variant destroys the canonical splice acceptor site in intron 61, and is expected to cause abnormal gene splicing. The variant is observed in 15/33530 (0.045%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). In summary, we consider c.12067-2 A>G to be pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000666727	SCV000893284	pathogenic	Usher syndrome, type 2A; Retinitis pigmentosa 39	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000412841	SCV000933043	pathogenic	not provided	2019-12-06	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 and likely results in an absent or disrupted protein product. This variant is present in population databases (rs397517978, ExAC 0.07%). This variant has been observed to segregate with Usher syndrome in a family and has been reported in individuals affected with Usher syndrome (PMID: 18452394, 25404053, 22004887) or pericentral retinitis pigmentosa (PMID: 28981474). 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, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). 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
Counsyl	RCV000983997	SCV000791074	pathogenic	Retinitis pigmentosa 39	2017-04-24	no assertion criteria provided	clinical testing
Sharon lab,Hadassah-Hebrew University Medical Center	RCV001003259	SCV001161341	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research