Submissions for variant NM_206933.4(USH2A):c.4378G>A (p.Gly1460Arg)

gnomAD frequency: 0.00001  dbSNP: rs139311927

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155330	SCV000205016	uncertain significance	not specified	2020-08-14	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly1460Arg variant in USH2A has been reported in two individuals with isolated retinitis pigmentosa (Wang 2014 PMID 24154662, Lenassi 2015 PMID 25649381). In one individual, a second missense variant in USH2A was identified, and the two variants segregated with the isolated retinitis pigmentosa in one sibling (Wang 2014 PMID 24154662). In the remaining individual, a second truncating USH2A variant was also identified (Lenassi 2015 PMID 25649381). It has also been previously reported in the heterozygous state by our laboratory in two individuals with sensorineural hearing loss. This variant has also been identified in 0.004% (4/113294) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PP1, PM3_Supporting.
Fulgent Genetics, Fulgent Genetics	RCV000765070	SCV000896271	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-10-31	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376456	SCV001573604	uncertain significance	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.4378G>A 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. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381659	SCV001580148	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1460 of the USH2A protein (p.Gly1460Arg). This variant is present in population databases (rs139311927, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive inherited retinal dystrophy (PMID: 24154662, 25649381). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178581). Invitae Evidence 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 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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001376456	SCV004207718	likely pathogenic	Retinitis pigmentosa 39	2024-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479024	SCV004222875	likely pathogenic	Usher syndrome	2023-11-17	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.4378G>A (p.Gly1460Arg) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of 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 1.6e-05 in 250642 control chromosomes. c.4378G>A has been reported in the literature in individuals affected with retinitis pigmentosa (Wang_2014, Lenassi_2015, Zhu_2021), and some were compound heterozygous with likely pathogenic variants. 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. The following publications have been ascertained in the context of this evaluation (PMID: 24154662, 25649381, 32675063). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=1) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc.	RCV001276257	SCV001462269	uncertain significance	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732718	SCV005360358	likely pathogenic	USH2A-related disorder	2024-09-11	no assertion criteria provided	clinical testing	The USH2A c.4378G>A variant is predicted to result in the amino acid substitution p.Gly1460Arg. This variant has been reported along with a second variant in USH2A in individuals with retinitis pigmentosa (Wang et al. 2014. PubMed ID: 24154662; Lenassi et al. 2015. PubMed ID: 25649381; Qu et al. 2020. PubMed ID: 31904091). We have also observed this variant with a second USH2A variant in a number of patients with hearing loss or inherited retinal disease (PreventionGenetics internal data). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.