Submissions for variant NM_206933.4(USH2A):c.5698T>G (p.Cys1900Gly)

gnomAD frequency: 0.00004  dbSNP: rs201026468

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041864	SCV000065560	uncertain significance	not specified	2017-06-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Cys1900Gly va riant in USH2A has been reported as a homozygous variant in one individual with Usher syndrome, who was also homozygous for another variant of uncertain clinica l significance in USH2A (Bonnet 2016). The variant was also reported in two indi viduals with hearing loss and one individual with retinitis pigmentosa; however these individuals were heterozygous for the variant and did not carry a second v ariant (Haer-Wigman 2017, unpublished LMM data, ClinVar Variation ID: 4853). Thi s variant has also been identified in 0.38% (117/30776) of South Asian chromosom es, including one homozygous individual, by the genome Aggregation Database (gno mAD,http://gnomad.broadinstitute.org; dbSNP rs201026468). Computational predicti on tools and conservation analysis suggest that this variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, while the clinical significance of the p.Cys1900Gly variant is unc ertain, these data suggest that it is more likely to be benign.
Invitae	RCV000903235	SCV001047693	likely benign	not provided	2024-01-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001810413	SCV002060200	uncertain significance	Usher syndrome type 2A	2021-10-01	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.5698T>G(C1900G) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. C1900G has been observed in cases with relevant disease (PMID: 28224992, 27460420). Functional assessments of this variant are not available in the literature. C1900G has been observed in population frequency databases (gnomAD: SAS 0.38%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.5698T>G(C1900G) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041864	SCV002104142	uncertain significance	not specified	2022-02-18	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.5698T>G (p.Cys1900Gly) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 250564 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00048 vs 0.011), allowing no conclusion about variant significance. c.5698T>G has been reported in the literature as non-informative genotypes in individuals affected with and/or undergoing diagnostic exome sequencing for Usher Syndrome/visual impairment (example, Bonnet_2016, Haer-Wigman_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000903235	SCV003828072	uncertain significance	not provided	2019-06-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000903235	SCV001550102	uncertain significance	not provided		no assertion criteria provided	clinical testing	The USH2A p.C1900G variant was identified in a homozygous individual with Usher syndrome, as well as a heterozygous individual with retinitis pigmentosa (Bonnet_2016_PMID: 27460420; Haer-Wigman_2017_PMID: 28224992). The variant was identified in dbSNP (ID: rs201026468) and in ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine and Counsyl; and as likely benign by Invitae). The variant was identified in control databases in 120 of 250564 chromosomes (1 homozygous) at a frequency of 0.0004789, and was observed at the highest frequency in the South Asian population in 117 of 30610 chromosomes (1 homozygous) (freq: 0.003822) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.C1900 residue is conserved in mammals and more distantly related organisms, however computational analyses predicting the impact of this variant on protein function are not available. 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.