ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.7334C>T (p.Ser2445Phe) (rs41315579)

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Total submissions: 8
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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, Partners HealthCare 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 2020-11-11 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)
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.

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