Submissions for variant NM_206933.4(USH2A):c.3532C>G (p.Pro1178Ala)

gnomAD frequency: 0.00003  dbSNP: rs372081834

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000356379	SCV000354130	uncertain significance	Retinitis pigmentosa	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000394505	SCV000354131	likely benign	Usher syndrome type 2A	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000611914	SCV000713613	benign	not specified	2017-08-23	criteria provided, single submitter	clinical testing	p.Pro1178Ala in exon 17 of USH2A: This variant is not expected to have clinical significance because it has been identified in 1.24% (205/16512) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs372081834).
Invitae	RCV000943840	SCV001089796	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000943840	SCV001158267	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000394505	SCV001716343	likely benign	Usher syndrome type 2A	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001578966	SCV001806334	uncertain significance	Retinitis pigmentosa 39	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000943840	SCV001940531	benign	not provided	2018-11-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31047384, 33120657)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000611914	SCV002500245	benign	not specified	2022-03-08	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.3532C>G (p.Pro1178Ala) results in a non-conservative amino acid change in 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 0.0014 in 251032 control chromosomes in the gnomAD database, including 4 homozygotes. This frequency is almost close to that estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0014 vs 0.011), supporting a benign outcome. To our knowledge, no penetrant association of c.3532C>G in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments with a predominant consensus as benign/likely benign (n=7) (VUS, n=2). Based on the evidence outlined above, the variant was classified as benign.
Natera, Inc.	RCV000394505	SCV001459759	benign	Usher syndrome type 2A	2020-04-30	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000943840	SCV001924308	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000943840	SCV001959269	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000943840	SCV001968557	likely benign	not provided		no assertion criteria provided	clinical testing