Submissions for variant NM_206933.4(USH2A):c.7334C>T (p.Ser2445Phe)

gnomAD frequency: 0.00001  dbSNP: rs41315579

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171531	SCV001334316	benign	Usher syndrome	2020-03-18	reviewed by expert panel	curation	The filtering allele frequency (the lower threshold of the 95% CI of 197/30616) of the p.Ser2445Phe variant in the USH2A gene is 0.57% for South Asian chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041907	SCV000065603	uncertain significance	not specified	2011-02-14	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Ser2445Phe variant in USH2A has been previously reported in dbSNP (rs41315579) without freq uency information (one heterozygous submission). The Ser2445 residue is conserve d in several mammals and distant species up to Zebrafish but is replaced by alan ine in mouse and rat. Biochemical and computational analyses (PolyPhen, SIFT and AlignGVGD) suggest that the variant may impact the protein. In addition, the id entification of this variant in this patient with a likely pathogenic variant in USH2A and a phenotype consistent with Usher type 2, increases the likelihood th at this variant is disease-causing. In summary, the clinical significance of thi s variant cannot be determined with certainty at this time; however based upon t he arguments described above, we would lean towards a more likely pathogenic rol e.
Counsyl	RCV000667058	SCV000791451	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-10-09	criteria provided, single submitter	clinical testing
Invitae	RCV000923961	SCV001069460	benign	not provided	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000923961	SCV001773588	likely benign	not provided	2019-08-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28041643)
Fulgent Genetics, Fulgent Genetics	RCV000667058	SCV002804907	likely benign	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-05-05	criteria provided, single submitter	clinical testing
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV003224127	SCV003920700	uncertain significance	Bardet-Biedl syndrome	2023-06-02	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000923961	SCV004184011	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	USH2A: BS2
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504969	SCV000598825	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001271984	SCV001453612	likely benign	Usher syndrome type 2A	2020-01-06	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000923961	SCV001548852	uncertain significance	not provided		no assertion criteria provided	clinical testing	The USH2A p.Ser2445Phe variant was identified in 1 of 1444 proband chromosomes (frequency: 0.00069) from individuals with inherited retinal disease (Carss_2017_PMID:28041643). The variant was identified in dbSNP (ID: rs41315579) and ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine and Counsyl, and as likely pathogenic by NIHR Bioresource Rare Diseases, University of Cambridge). The variant was identified in control databases in 211 of 250880 chromosomes (2 homozygous) at a frequency of 0.000841 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 197 of 30616 chromosomes (freq: 0.006435), Other in 2 of 6114 chromosomes (freq: 0.000327), Latino in 3 of 34556 chromosomes (freq: 0.000087), European (non-Finnish) in 8 of 113262 chromosomes (freq: 0.000071) and East Asian in 1 of 18382 chromosomes (freq: 0.000054), but was not observed in the African, Ashkenazi Jewish, or European (Finnish) populations. Although the p.Ser2445 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.