Submissions for variant NM_206933.4(USH2A):c.4251G>T (p.Gln1417His)

dbSNP: rs2102460239

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001360099	SCV001555999	pathogenic	not provided	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change affects codon 1417 of the USH2A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the USH2A protein. This variant also falls at the last nucleotide of exon 19, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of USH2A-related conditions (PMID: 16963483, 32037395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1051986). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Genome-Nilou Lab	RCV001587370	SCV001821887	uncertain significance	Usher syndrome type 2A	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001587371	SCV001821898	uncertain significance	Retinitis pigmentosa 39	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815453	SCV005070570	likely pathogenic	Retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699335	SCV005204362	uncertain significance	not specified	2024-06-12	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.4251G>T (p.Gln1417His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250690 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4251G>T has been reported in the literature in individuals affected with Usher Syndrome and related conditions (Cremers_2007, Zampaglione_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16963483, 32037395). ClinVar contains an entry for this variant (Variation ID: 1051986). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005005877	SCV005638304	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-06-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001587370	SCV002093903	uncertain significance	Usher syndrome type 2A	2021-02-25	no assertion criteria provided	clinical testing