Submissions for variant NM_206933.4(USH2A):c.6722C>T (p.Pro2241Leu)

dbSNP: rs1057518826

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042036	SCV001205694	pathogenic	not provided	2023-10-13	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 2241 of the USH2A protein (p.Pro2241Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with retinitis pigmentosa and/or Usher syndrome (PMID: 25999674, 26927203, 27318125, 28224992; Invitae). ClinVar contains an entry for this variant (Variation ID: 560523). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. This variant disrupts the p.Pro2241 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 27460420), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001724131	SCV001950405	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Pro2241Leu 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: PM2, PP3, PM3, PM1. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
3billion	RCV002283505	SCV002573090	likely pathogenic	Retinitis pigmentosa 39	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000560523). Different missense changes at the same codon (p.Pro2241His, p.Pro2241Thr) have been reported to be associated with USH2A -related disorder (ClinVar ID: VCV000374001 / PMID: 27460420). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469254	SCV002766559	likely pathogenic	Usher syndrome	2022-11-05	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.6722C>T (p.Pro2241Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251092 control chromosomes (gnomAD). c.6722C>T has been reported in the literature as a biallelic genotype in individuals affected with Usher Syndrome (e.g. van Huet_2015, Hartel_2016, Pierrache_2016, Haer-Wigman_2017, Reurink_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: three classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV002283505	SCV004181623	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000678653	SCV004181624	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002283505	SCV004200748	pathogenic	Retinitis pigmentosa 39	2024-03-18	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678653	SCV000804744	likely pathogenic	Usher syndrome type 2A	2016-09-01	no assertion criteria provided	clinical testing