ClinVar Miner

Submissions for variant NM_015404.4(WHRN):c.33C>G (p.Ser11Arg) (rs45527543)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038895 SCV000062573 likely benign not specified 2015-09-17 criteria provided, single submitter clinical testing p.Ser11Arg in exon 1 of DFNB31 variant is not expected to have clinical signific ance because it has been identified in 0.5% (10/1860) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s45527543). In addition, computational prediction tools and conservation data su ggest the variant may not impact the protein.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725335 SCV000336117 uncertain significance not provided 2015-10-08 criteria provided, single submitter clinical testing
GeneDx RCV000725335 SCV000521013 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing The S11R variant in the WHRN gene has been reported previously in 1 of 54 Caucasian patients with sensorineural deafness, retinal degeneration, and Usher syndrome; however, these patients were tested for 9 Usher syndrome genes, and this individual also harbored two frameshift variants in the ADGRV1 gene present in trans (Bonnet et al., 2011). The S11R variant is observed in 21/5650 (0.37%) alleles from individuals of Ashkenazi Jewish background in large population cohorts, and in 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016). The S11R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret S11R as a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000725335 SCV000885277 uncertain significance not provided 2017-08-14 criteria provided, single submitter clinical testing The p.Ser11Arg variant (rs45527543) has been previously reported in a patient with a clinical diagnosis of Usher Syndrome II (Bonnet 2011). However, the patient reported in Bonnet et al (2011) carried no other relevant variants in the WHRN gene, but did harbor two pathogenic variants in ADGRV1 in a trans heterozygous configuration. This variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Ashkenazi Jewish populations of 0.37% (identified in 21 out of 5,650 chromosomes), and is listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 45677). The serine at codon 11 is moderately conserved considering 12 species (Alamut software v2.9), and computational analyses suggest this variant has/does not have a significant effect on WHRN protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Ser11Arg variant cannot be determined with certainty.
Mendelics RCV000988244 SCV001137893 benign Retinitis pigmentosa-deafness syndrome 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000725335 SCV001228175 uncertain significance not provided 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 11 of the WHRN protein (p.Ser11Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. While this variant is present in population databases (rs45527543), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with Usher syndrome along with biallelic variants in a different gene (PMID: 30245029). ClinVar contains an entry for this variant (Variation ID: 45677). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001168207 SCV001330783 uncertain significance Deafness, autosomal recessive 31 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001168208 SCV001330784 uncertain significance Usher syndrome, type 2D 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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