Submissions for variant NM_206933.4(USH2A):c.9949C>T (p.Arg3317Cys)

gnomAD frequency: 0.00006  dbSNP: rs200696560

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051736	SCV001215906	uncertain significance	not provided	2022-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3317 of the USH2A protein (p.Arg3317Cys). This variant is present in population databases (rs200696560, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 848058). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV001051736	SCV002032613	uncertain significance	not provided	2021-12-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387958	SCV004100198	uncertain significance	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.9949C>T (p.Arg3317Cys) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251216 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (5.2e-05 vs 0.011), allowing no conclusion about variant significance. c.9949C>T has been reported in the literature in individuals affected with unspecified retinal disorder (Karali_2022) and Retinitis Pigmentosa (Reurink_2023). These data do not allow any conclusion about variant significance. 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: 36460718, 36785559). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV003455224	SCV004182629	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001276952	SCV004182632	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276952	SCV001463645	uncertain significance	Usher syndrome type 2A	2020-01-11	no assertion criteria provided	clinical testing