Submissions for variant NM_206933.4(USH2A):c.6233C>G (p.Pro2078Arg)

gnomAD frequency: 0.00023  dbSNP: rs150230450

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001252668	SCV001428427	uncertain significance	Usher syndrome	2020-06-24	reviewed by expert panel	curation	The c.6233C>G (p.Pro2078Arg) variant in USH2A was present in 0.39% (lower bound of the 95% CI of 50/10070) of Ashkenazi Jewish alleles in gnomAD v3. Although this population frequency is high enough to meet BS1, this evidence was downgraded to BS1_Supporting because this variant is likely a founder mutation in the Ashkenazi Jewish population. The p.Pro2078Arg variant was observed in one proband with retinitis pigmentosa and a second pathogenic variant in USH2A (PM3_Supporting; Hadassah-Hebrew University Medical Center internal data, ClinVar SCV001161352.1). It has also been seen in at least 4 probands without a second variant identified in USH2A (Laboratory for Molecular Medicine and Invitae internal data, ClinVar SCV000201902.5, SCV001068267.2). The REVEL computational prediction tool produced a score of 0.702, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, PM3_Supporting, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152606	SCV000201902	uncertain significance	not specified	2013-10-17	criteria provided, single submitter	clinical testing	The Pro2078Arg variant in USH2A has not been reported in individuals with hearin g loss, but has been identified in 0.02% (1/4406) of African American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs150230450). Computational analyses (biochemical amino acid properties, conse rvation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Pro2078Arg variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, additional data is needed to determine the clinica l significance of this variant.
Counsyl	RCV000664998	SCV000789048	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2016-12-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000922822	SCV001068267	likely benign	not provided	2024-05-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000922822	SCV004125614	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000922822	SCV005078111	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	Reported in association with retinitis pigmentosa in published literature (PMID: 31456290); however, limited clinical and segregation information provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31456290)
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003269	SCV001161352	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001273039	SCV001455622	uncertain significance	Usher syndrome type 2A	2020-01-17	no assertion criteria provided	clinical testing