Submissions for variant NM_206933.4(USH2A):c.838C>T (p.Leu280Phe)

dbSNP: rs2037760521

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001346115	SCV001540290	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. ClinVar contains an entry for this variant (Variation ID: 1042201). This missense change has been observed in individual(s) with Usher syndrome (PMID: 17405132, 24944099). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 280 of the USH2A protein (p.Leu280Phe).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553665	SCV001774602	likely pathogenic	Usher syndrome	2021-07-21	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.838C>T (p.Leu280Phe) results in a non-conservative amino acid change located in the LamG-like jellyroll fold (IPR006558)/Laminin N-terminal domain of the encoded protein sequence. Leucine residue at position 280 is highly conserved among 12 orthologs and has been predicted to be the N2 residue of an alpha helix with the replacement by a Phenylalanine as likely to alter the secondary structure of the Usherin protein (Baux_2007). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250912 control chromosomes. c.838C>T has been reported in the literature as distinct genotypes in at-least two individuals affected with Usher Syndrome (example, Baux_2007, Baux_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing one overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001346115	SCV002818763	likely pathogenic	not provided	2022-12-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17405132, 24944099)
Genome-Nilou Lab	RCV003449970	SCV004182940	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing