Submissions for variant NM_206933.4(USH2A):c.236_239dup (p.Gln81fs)

dbSNP: rs1553258097

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668189	SCV000792751	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-07-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389817	SCV001591301	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln81Tyrfs*28) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with USH2A-related disease (PMID: 10738000, 24367894, 29490346). This variant is also known as 239-242insCGTA. ClinVar contains an entry for this variant (Variation ID: 552849). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298727	SCV002599050	pathogenic	Usher syndrome	2022-09-19	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.236_239dupGTAC (p.Gln81TyrfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250878 control chromosomes. c.236_239dupGTAC has been reported in the literature in multiple individuals affected with Usher Syndrome. These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV003451673	SCV004182997	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001835908	SCV004182998	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003451673	SCV004208389	pathogenic	Retinitis pigmentosa 39	2024-02-01	criteria provided, single submitter	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003291	SCV001161374	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001835908	SCV002094033	pathogenic	Usher syndrome type 2A	2020-06-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004533469	SCV004746832	pathogenic	USH2A-related disorder	2023-12-05	no assertion criteria provided	clinical testing	The USH2A c.236_239dupGTAC variant is predicted to result in a frameshift and premature protein termination (p.Gln81Tyrfs*28). This variant was reported in multiple individuals with autosomal recessive Usher syndrome (also described as c.239_240insGTAC; Adato. 2000. PubMed ID: 10738000; Behar. 2013. PubMed ID: 24367894; Khalaileh. 2018. PubMed ID: 29490346; Bahena. 2021. PubMed ID: 34148116). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in USH2A are expected to be pathogenic. This variant is interpreted as pathogenic.