Submissions for variant NM_206933.4(USH2A):c.4106C>T (p.Ser1369Leu)

gnomAD frequency: 0.00019  dbSNP: rs201709513

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041837	SCV000065533	uncertain significance	not specified	2016-10-25	criteria provided, single submitter	clinical testing	The p.Ser1369Leu variant in USH2A has been previously reported in three individu als with Usher syndrome, one individual with retinitis pigmentosa, and one indiv idual with hearing loss (Colombo 2015, Cremers 2007, Dad 2015, Wang 2014, LMM da ta). In the proband with retinitis pigmentosa, a second variant of uncertain si gnificance was identified and the two variants segregated in an affected sibling ; however, cis/trans testing was not performed (Wang 2014). In the remaining pr obands, a pathogenic variant affecting the remaining copy of USH2A was not ident ified. This variant has been identified in 13/65610 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201 709513); however, this frequency is not high enough to rule out a pathogenic rol e. The serine (Ser) at position 1369 is not conserved through species, with 2 m ammals (squirrel and brush-tailed rat) and 2 bird species having a leucine, sugg esting that this change may be tolerated. Additional computational prediction t ools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser1369Leu variant is uncertain.
Eurofins Ntd Llc (ga)	RCV000726718	SCV000702404	uncertain significance	not provided	2016-11-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000665274	SCV000789366	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-01-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726718	SCV001234991	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1369 of the USH2A protein (p.Ser1369Leu). This variant is present in population databases (rs201709513, gnomAD 0.08%). This missense change has been observed in individual(s) with USH2A-related disease (PMID: 20591486, 24154662, 26927203, 27957503, 31047384; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48511). 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 with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074345	SCV001239920	likely pathogenic	Retinal dystrophy	2019-07-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307377	SCV001448380	likely pathogenic	Usher syndrome	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.4106C>T (p.Ser1369Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain (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 0.00016 in 250578 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00016 vs 0.011), allowing no conclusion about variant significance. c.4106C>T has been reported in the literature in individuals affected with features of Usher Syndrome and with retinitis pigmentosa (RP) (e.g. Cremers_2007, Zhao_2015, Dad_2016). Furthermore, the variant was shown to co-segregate with retinitis pigmentosa in siblings from two different families (Wang_2014, Comander_2017). At-least one putative "in cis" co-occurrence of the variant with either of two other pathogenic variants (c.9270C>A, p.C3090X or c.6159delA, p.E2054KfsX10; phase unknown) has been reported in one RP patient (Wang_2014), while in another instance following internal testing the variant was reported in cis (confirmed via parental studies) with a pathogenic variant (c.6159delA, p.E2054KfsX10) in one individual. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; Pathogenic/Likely pathogenic, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376516	SCV001573693	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.4106C>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: PS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
DBGen Ocular Genomics	RCV001376516	SCV001816009	likely pathogenic	Retinitis pigmentosa 39	2021-06-23	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723629	SCV001950404	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Ser1369Leu variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Revvity Omics, Revvity	RCV000726718	SCV002021604	likely pathogenic	not provided	2021-03-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003326116	SCV004032323	pathogenic	Usher syndrome type 2A	2023-08-22	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PM1,PM2_SUP; Identified as compund heterozygous with NM_206933.4:c.2299del
CeGaT Center for Human Genetics Tuebingen	RCV000726718	SCV004125620	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	USH2A: PM2, PP1, BP4
Genetics and Molecular Pathology, SA Pathology	RCV001376516	SCV004175466	likely pathogenic	Retinitis pigmentosa 39	2021-02-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732594	SCV005358052	likely pathogenic	USH2A-related disorder	2024-03-22	no assertion criteria provided	clinical testing	The USH2A c.4106C>T variant is predicted to result in the amino acid substitution p.Ser1369Leu. This variant has been reported in multiple unrelated patients with Usher syndrome or retinitis pigmentosa (Table S4, Pierrache et al. 2016. PubMed ID: 26927203; Dad et al. 2015. PubMed ID: 25804404; Comander et al. 2017. PubMed ID: 28981474; Wang et al. 2014. PubMed ID: 24154662; Colombo et al. 2015. PubMed ID: 26075083; Table S2, Zampaglione et al 2020. PubMed ID: 32037395; Molina-Ramírez et al 2020. PubMed ID: 32176120; Tables S5 and S7, Colombo et al 2021. PubMed ID: 33576794). This variant has been reported in conjunction with a pathogenic USH2A variant in multiple individuals, however, segregation analysis to determine phase was not reported for all cases (Hariri et al. 2017. PubMed ID: 31047384; Yohe et al 2019. PubMed ID: 31816670; Molina-Ramírez et al. 2020. PubMed ID: 32176120; Colombo et al. 2021. PubMed ID: 33576794; Lynn et al. 2022. PubMed ID: 36672815; Panneman et al. 2023. PubMed ID: 36819107). This variant was also shown to segregate with disease in siblings from two unrelated families with retinitis pigmentosa (Wang et al. 2013. PubMed ID: 24154662; Comander et al. 2017. PubMed ID: 28981474). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/48511/). This variant is interpreted as likely pathogenic.