ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.3408T>A (p.Ser1136Arg) (rs1064793287)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484519 SCV000565646 likely pathogenic not provided 2014-08-26 criteria provided, single submitter clinical testing A novel S1136R variant that is likely pathogenic was identified in the USH2A gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The S1136R variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The S1136R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position, in the Fibronectin type-III domain, that is well-conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues and at the same codon (G1132D and S1136N) have been reported in the Human Gene Mutation Database in association with Usher syndrome (Stenson et al., 2009), supporting the functional importance of this residue and region of the protein. The conservative amino acid change at the same codon (S1136N) was published as probably pathogenic (Le Quesne Stabej et al., 2012). Therefore, this is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded.
Laboratory for Molecular Medicine, Partners HealthCare 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.

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