Submissions for variant NM_206933.4(USH2A):c.14453C>T (p.Pro4818Leu)

gnomAD frequency: 0.00011  dbSNP: rs143344549

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000613330	SCV000710852	likely pathogenic	Rare genetic deafness	2016-12-22	criteria provided, single submitter	clinical testing	The p.Pro4818Leu variant in USH2A has been reported in 5 individuals with Usher syndrome and 1 individual with retinitis pigmentosa (Aller 2006, Garcia-Garcia 2 011, Jaijo 2010, McGee 2010, Zhao 2015). Two individuals with Usher syndrome wer e confirmed to have a different truncating variant affecting the other copy of U SH2A. This variant has been identified in several populations by the Exome Aggre gation Consortium with the highest frequency of 3/16510 in South Asian chromosom es (ExAC, http://exac.broadinstitute.org; dbSNP rs143344549). However, this is low enough to be consistent with a recessive carrier frequency. Computational pr ediction tools and conservation analysis suggest that the p.Pro4818Leu variant m ay impact the protein. In summary, although additional studies are required to f ully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome based on its occurrence in trans with another pathogenic variant in USH2A in multiple unrelated affected individuals.
Mendelics	RCV000986515	SCV001135530	likely pathogenic	Usher syndrome type 2A	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001040115	SCV001203673	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4818 of the USH2A protein (p.Pro4818Leu). This variant is present in population databases (rs143344549, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 17085681, 22004887, 25472526, 29899460). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 504509). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376397	SCV001573520	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.14453C>T 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, PM3, PP1-M. Based on this evidence we have classified this variant as Likely Pathogenic.
GeneDx	RCV001040115	SCV002584334	likely pathogenic	not provided	2022-10-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 17085681, 22004887, 30081015, 19683999, 20507924, 20591486, 25472526, 29899460, 30245926, 31589614, 34426522, 31980526, 31429209)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000986515	SCV002766819	pathogenic	Usher syndrome type 2A	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 39 (MIM#613809) and type 2A Usher syndrome (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 17 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many individuals with autosomal recessive retinitis pigmentosa or Usher syndrome (PMIDs: 22004887, 25472526, 29899460, 30081015, 32098976). It has also been reported as likely pathogenic/pathogenic in ClinVar and Deafness Variation Database. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002506444	SCV002811686	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-03-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001040115	SCV003826097	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155245	SCV003844830	pathogenic	Usher syndrome	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.14453C>T (p.Pro4818Leu) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence, altering a highly conserved residue (HGMD). 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 6.4e-05 in 251372 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (6.4e-05 vs 0.011), allowing no conclusion about variant significance. c.14453C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa or Usher Syndrome (Aller_2006, Garcia-Garcia_2011, Huang_2018, Jaijo_2010, Jauregui_2020, Zhao_2015), and several patients were reported as compound heterozygous with other (likely) pathogenic variants. 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. Seven subitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV001376397	SCV004183065	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000986515	SCV004183066	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376397	SCV004208171	likely pathogenic	Retinitis pigmentosa 39	2023-10-16	criteria provided, single submitter	clinical testing