Submissions for variant NM_206933.4(USH2A):c.842C>A (p.Thr281Lys)

dbSNP: rs2037760415

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002570628	SCV003524128	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr281 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 26856745, 30902645), which suggests that this may be a clinically significant amino acid residue. 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: 979017). This missense change has been observed in individual(s) with inherited retinal dystrophy and/or Usher syndrome (PMID: 22135276, 26355662, 26667666). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 281 of the USH2A protein (p.Thr281Lys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323835	SCV004029985	likely pathogenic	Usher syndrome	2023-07-07	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.842C>A (p.Thr281Lys) results in a non-conservative amino acid change located in the LamG-like jellyroll fold (IPR006558) and N-terminal (IPR008211) domains of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250902 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.842C>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Usher Syndrome (e.g., LeQuesneStabej_2012, Ge_2015, Patel_2016). 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. The following publications have been ascertained in the context of this evaluation (PMID: 26667666, 26355662, 22135276). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV003449817	SCV004182939	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469488	SCV004206445	likely pathogenic	Retinitis pigmentosa 39	2022-01-18	criteria provided, single submitter	clinical testing
Faculty of Health Sciences, Beirut Arab University	RCV001257908	SCV001434724	pathogenic	Autosomal recessive retinitis pigmentosa	2015-09-10	no assertion criteria provided	literature only