Submissions for variant NM_206933.4(USH2A):c.821G>A (p.Arg274Gln)

gnomAD frequency: 0.00003  dbSNP: rs727504721

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156012	SCV000205724	uncertain significance	not specified	2013-09-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg274Gln varia nt in USH2A has not been reported in individuals with hearing loss or in large p opulation studies. The arginine (Arg) residue at position 274 is not well conser ved across species with cat and shrew having a glutamine (Gln) at that position. However, computational data (SIFT, PolyPhen2, AlignGVGD) provide conflicting pr edictions on the impact of the variant. In summary, the clinical significance of this variant cannot be determined with certainty; however based upon the conser vation data, we would lean towards a more likely benign role.
Counsyl	RCV000673498	SCV000798706	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-03-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001731487	SCV001982230	uncertain significance	not provided	2024-04-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36460718, 34948090, 27460420)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001731487	SCV003283600	likely pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 274 of the USH2A protein (p.Arg274Gln). This variant is present in population databases (rs727504721, gnomAD 0.006%). This missense change has been observed in individual(s) with inherited retinal dystrophy and/or Usher syndrome (PMID: 27460420, 34948090, 36460718; internal data). ClinVar contains an entry for this variant (Variation ID: 179225). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Arg274 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28041643; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003462061	SCV004208317	likely pathogenic	Retinitis pigmentosa 39	2024-03-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000673498	SCV005643089	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-06-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831971	SCV002094012	uncertain significance	Usher syndrome type 2A	2020-10-14	no assertion criteria provided	clinical testing