Submissions for variant NM_206933.4(USH2A):c.3408T>A (p.Ser1136Arg)

gnomAD frequency: 0.00001  dbSNP: rs1064793287

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484519	SCV000565646	likely pathogenic	not provided	2022-12-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A different missense change at this residue (S1136N) has been classified as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840537.3; Oza et al., 2018); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30311386)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000599950	SCV000713491	likely pathogenic	Rare genetic deafness	2017-11-01	criteria provided, single submitter	clinical testing	The p.Ser1136Arg variant in USH2A has been reported in 1 infant with congenital mild to moderate hearing loss who was compound heterozygous for a second USH2A v ariant, and the two variants segregated in an affected sibling. This variant has also been reported in ClinVar (Variation ID: 418534). Another amino acid change at the same position has been reported in 1 individual with Usher syndrome who was compound heterozygous for a second pathogenic USH2A variant (Le Quesne Stabe j 2012, Bonnet 2016). The p.Ser1136Arg variant has been identified in 1/33578 La tino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org/; dbSNP rs1064793287). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. Computational prediction tools and conservation analyses su ggest that this variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP3, PM3_Supporting.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000484519	SCV000884862	uncertain significance	not provided	2018-03-12	criteria provided, single submitter	clinical testing	The USH2A c.3408T>A; p.Ser1136Arg variant, to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. However, another variant affecting the same codon, Ser1136Asn, was found in a patient with Usher syndrome (Le Quesne Stabej 2012). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.0004% (identified on 1 out of 245,946 chromosomes) and is classified as likely pathogenic in ClinVar (ID: 418534). The serine at position 1136 is moderately conserved, considering 12 species, and computational analyses of the effects of the p.Ser1136Arg variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: probably damaging). Although the available information suggests that it may be pathogenic, the clinical significance of the p.Ser1136Arg variant cannot be determined with certainty.
Invitae	RCV000484519	SCV002209315	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1136 of the USH2A protein (p.Ser1136Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of USH2A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 418534). 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 expected to disrupt USH2A protein function with a positive predictive value of 95%. This variant disrupts the p.Ser1136 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22135276, 25991456, 27460420, 27957503, 28512305, 30718709). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222521	SCV002500600	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.3408T>A (p.Ser1136Arg) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251178 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3408T>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One publication reports one compound heterozygous Usher Syndrome patient carrying a different likely pathogenic missense variant (ClinVar:133312) on the same codon (p.Ser1136Asn, Le Quesne Stabej_2012). While this could suggest that the variant of interest is also likely pathogenic, there are large biochemical differences between Asn and Arg, and thus these two substitutions cannot be directly compared. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain signficance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.