Submissions for variant NM_206933.4(USH2A):c.920_923dup (p.His308fs)

dbSNP: rs397518043

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824800	SCV000065637	pathogenic	Rare genetic deafness	2014-07-08	criteria provided, single submitter	clinical testing	The His308fs variant has been reported in many probands with Usher syndrome type II, many of whom were homozygous or compound heterozygous (Weston 2000, Sandber g 2008, Aller 2004, Dreyer 2008, Dreyer 2000, Jaijo 2009, Leroy 2001, Ouyang 200 4, Pennings 2004, Seyedahmadi 2004). In addition, the His308fs variant is predic ted to cause a frameshift, which alters the protein's amino acid sequence beginn ing at codon 308 and leads to a premature stop codon 16 codons downstream. This alteration is then predicted to lead to a truncated or absent protein. In summar y, this variant meets our criteria to be classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000790675	SCV000231841	pathogenic	not provided	2015-04-24	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000041941	SCV000598152	pathogenic	Usher syndrome type 2A	2016-11-08	criteria provided, single submitter	clinical testing	This heterozygous variant in the USH2A gene (autosomal recessive transmission), was present in a female patient with Usher syndrome who also harbours a large deletion in the same gene (compound heterozygosity).
Mayo Clinic Laboratories, Mayo Clinic	RCV000041941	SCV000809063	pathogenic	Usher syndrome type 2A	2018-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000790675	SCV000949075	pathogenic	not provided	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His308Glnfs*16) 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 present in population databases (rs397518043, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with retinal dystrophy and Usher syndrome 2A (PMID: 10729113, 23940504, 26806561, 26969326). It has also been observed to segregate with disease in related individuals. This variant is also known as 921-922insCAGC. ClinVar contains an entry for this variant (Variation ID: 48615). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074427	SCV001240011	pathogenic	Retinal dystrophy	2019-08-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000790675	SCV001248866	pathogenic	not provided	2024-09-01	criteria provided, single submitter	clinical testing	USH2A: PM3:Very Strong, PVS1, PP1:Strong, PM2
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000411255	SCV001573542	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.920_923dup 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, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.
Genomics England Pilot Project, Genomics England	RCV000411255	SCV001760025	pathogenic	Retinitis pigmentosa 39		criteria provided, single submitter	clinical testing
GeneDx	RCV000790675	SCV001826002	pathogenic	not provided	2021-10-19	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23940504, 22848652, 11311042, 14970843, 15025721, 15241801, 15325563, 25333064, 26969326, 18273898, 18641288, 19683999, 24944099, 10729113, 28157192, 29953849, 31370859, 32050993, 31589614, 31980526, 32581362, 31266775, 10909849)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000505107	SCV001950395	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.His308GlnfsTer16 variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Revvity Omics, Revvity	RCV000790675	SCV002020839	pathogenic	not provided	2021-10-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV002226452	SCV002505563	pathogenic	Retinal dystrophy; Retinal degeneration	2022-03-22	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_206933.4:c.14219C>A._x000D_ Criteria applied: PVS1, PM3_VSTR, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505018	SCV002599049	pathogenic	Usher syndrome	2022-09-19	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.920_923dupGCCA (p.His308GlnfsX16) 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 allele was found at a frequency of 5.6e-05 in 250562 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (5.6e-05 vs 0.011), allowing no conclusion about variant significance. c.920_923dupGCCA has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Usher Syndrome (Wafa_2020, Mansard_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 16 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000411255	SCV004182927	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000041941	SCV004182928	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411255	SCV004207708	pathogenic	Retinitis pigmentosa 39	2024-03-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000041941	SCV004812147	pathogenic	Usher syndrome type 2A	2022-06-22	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_VSTR
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074427	SCV005068544	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000411255	SCV005368134	pathogenic	Retinitis pigmentosa 39	2022-03-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000041941	SCV000487444	pathogenic	Usher syndrome type 2A	2016-08-18	no assertion criteria provided	clinical testing
Counsyl	RCV000411255	SCV000487445	pathogenic	Retinitis pigmentosa 39	2016-08-18	no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505018	SCV000598839	pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505107	SCV000598840	pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000411255	SCV000804750	pathogenic	Retinitis pigmentosa 39	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000505107	SCV000926747	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV000041941	SCV001457326	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000790675	SCV001957753	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000790675	SCV001967629	pathogenic	not provided		no assertion criteria provided	clinical testing