Submissions for variant NM_206933.4(USH2A):c.3584G>T (p.Cys1195Phe)

gnomAD frequency: 0.00003  dbSNP: rs727504652

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155915	SCV000205626	uncertain significance	not specified	2013-09-27	criteria provided, single submitter	clinical testing	The Cys1195Phe variant in USH2A has not been previously reported in individuals with hearing loss or in large population studies. Computational analyses (bioch emical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do n ot provide strong support for or against an impact to the protein. In summary, a dditional data is needed to determine the clinical significance of this variant.
Counsyl	RCV000668970	SCV000793656	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-08-22	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000225490	SCV001240459	uncertain significance	Retinal dystrophy	2019-07-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098833	SCV001255224	uncertain significance	Usher syndrome type 2A	2018-01-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001098834	SCV001255225	uncertain significance	Retinitis pigmentosa	2018-01-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001227048	SCV001399384	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1195 of the USH2A protein (p.Cys1195Phe). This variant is present in population databases (rs727504652, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Usher syndrome (PMID: 27208204). ClinVar contains an entry for this variant (Variation ID: 179130). 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 not expected to disrupt USH2A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376535	SCV001573714	uncertain significance	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.3584G>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. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001376535	SCV004182327	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001098833	SCV004182328	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001227048	SCV005325285	uncertain significance	not provided	2023-11-28	criteria provided, single submitter	clinical testing	Reported with additional variants in a patient with Usher syndrome in published literature (PMID: 27145477); 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: 26927203, 35266249, 27145477, 27208204)
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000225490	SCV000282650	uncertain significance	Retinal dystrophy		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001098833	SCV002093928	uncertain significance	Usher syndrome type 2A	2020-02-23	no assertion criteria provided	clinical testing