Submissions for variant NM_206933.4(USH2A):c.6446C>A (p.Pro2149Gln)

gnomAD frequency: 0.00001  dbSNP: rs869312182

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171538	SCV001334323	likely pathogenic	Usher syndrome	2025-01-15	reviewed by expert panel	curation	The c.6446C>A (p.Pro2149Gln) variant in USH2A is a missense variant predicted to cause a substitution of proline by glutamine at amino acid 2149. This variant has been detected in 2 individuals with Usher syndrome. Both were compound heterozygotes for the variant and a pathogenic or likely pathogenic variant and 1 of those were confirmed in trans by parental testing (PMID : 29074561, 31836858). This variant has also been detected in two individuals with isolated retinitis pigmentosa without hearing loss or without additional information about their hearing status . Both were compound heterozygotes for this variant and a pathogenic alteration (PMID : 38219857 ; 28041643). Clingen HL VCEP group agreed to take into consideration two index cases reported with isolated RP, compound heterozygote for this variant and the well known pathogenic c.2276G>A alteration, allowing to PM3_Srong criteria. At least one individual has a phenotype of hearing loss and retinitis pigmentosa, which is consistent with Usher syndrome type II (PP4 ; PMID: 32176120). The filtering allele frequency (the lower threshold of the 95% CI) of the c.6446C>A (p.Pro2149Gln) is 0.0002620% chromosomes by gnomAD v4.1.0 (non-Finnish Europeans), which meets the ClinGen Hearing Loss VCEP threshold ≤ 0.007% for PM2_P. The computational predictor REVEL gives a score of 0.36, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive USH2A-related conditions (isolated RP and Usher syndrome type II) based on the ACMG/AMP criteria applied, as specified by the Clingen Hearing Loss Expert Panel : PM2_Supporting, PM3_Strong, PP4_Supporting. (Hearing Loss VCEP specifications version 2; 01/15/2025).
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210323	SCV000259095	likely pathogenic	Usher syndrome type 2A	2015-08-28	no assertion criteria provided	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000225553	SCV000282656	uncertain significance	Retinal dystrophy		no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505157	SCV000598820	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research