Submissions for variant NM_206933.4(USH2A):c.1663C>G (p.Leu555Val)

gnomAD frequency: 0.00080  dbSNP: rs35818432

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041795	SCV000065491	likely benign	not specified	2017-05-02	criteria provided, single submitter	clinical testing	p.Leu555Val in exon 10 of USH2A: This variant is not expected to have clinical s ignificance because it has been identified 0.2% (24/10136) of Ashkenazi Jewish c hromosomes and in 0.2% (212/126366) of European chromosomes including 1 homozygo te by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs35818432). It has been reported in cis with another pathogenic variant in USH2A (Jaijo 2009, Vozzi 2011). A study has shown that the variant does not i mpact protein function (Bhattacharya 2004).
Eurofins Ntd Llc (ga)	RCV000041795	SCV000341464	likely benign	not specified	2016-05-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000415970	SCV000493631	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	USH2A: BP4, BS2
Invitae	RCV000415970	SCV001197469	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001101110	SCV001257681	uncertain significance	Usher syndrome type 2A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001003284	SCV001257682	uncertain significance	Retinitis pigmentosa	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376290	SCV001573380	uncertain significance	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.1663C>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: PM2, PP3, BP2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001101110	SCV001653456	uncertain significance	Usher syndrome type 2A	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000415970	SCV001940528	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25262649, 22995991, 14676276, 22004887, 21228398, 11311042, 27884173, 21569298, 29068140, 30245029, 31456290, 32707200)
Revvity Omics, Revvity	RCV000415970	SCV003828080	uncertain significance	not provided	2022-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041795	SCV004241424	uncertain significance	not specified	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.1663C>G (p.Leu555Val) results in a conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 1613940 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00097 vs 0.011), allowing no conclusion about variant significance. c.1663C>G has been reported in the literature in individuals affected with USH2A related conditions without strong evidence for causality (examples: Leory_2001, Colombo_2022, Karali_2022). One publication reported an individual affected with Usher syndrome with this variant and a second pathogenic variant c.1841-2A>G in homozygous state, supporting a benign role for this variant (example: Jaijo_2010). Multiple reports have classified this variant as benign (examples: Shearer_2014 and Azaiez_2018). At least one publication reports experimental evidence that this variant had no effect on usherin/collagen IV binding (example: Bhattacharya_2003). The following publications have been ascertained in the context of this evaluation (PMID: 11311042, 14676276, 19683999, 21569298, 25262649, 30245029, 29068140, 34781295, 36460718). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as benign/likely benign (n=6), VUS (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003284	SCV001161367	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001101110	SCV001459777	likely benign	Usher syndrome type 2A	2020-01-11	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000415970	SCV001924629	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000415970	SCV001959625	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000415970	SCV001975047	likely benign	not provided		no assertion criteria provided	clinical testing