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 2021-01-27 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
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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