ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2576G>A (p.Arg859Gln) (rs121912618)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000004787 SCV000450699 uncertain significance Autosomal dominant nonsyndromic deafness 6 2017-04-28 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 RCV000275899 SCV000450700 uncertain significance WFS1-Related Spectrum Disorders 2016-08-02 criteria provided, single submitter clinical testing The WFS1 c.2576G>A (p.Arg859Gln) missense variant has been reported in one study in which it was found in a heterozygous state in six of seven affected individuals spanning four generations from a family with low frequency sensorineural hearing loss and autoimmune disorders (Hildebrand et al. 2008). The p.Arg859Gln variant was absent from 177 controls but is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, but this is based on one allele only in a region of good sequence converage so the variant is presumed to be rare. The evidence for this variant is limited. The p.Arg859Gln variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for WFS1-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000480362 SCV000568516 uncertain significance not provided 2017-03-23 criteria provided, single submitter clinical testing The R859Q variant was reported to segregate with autosomal dominant sensorineural hearing loss in six affected individuals from a single family; however, an additional affected family member did not harbor R859Q (Hildebrand et al. 2008). The R859Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R859Q 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 where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant at the same position (R859P) showed completed segregation with autosomal dominant sensorineural hearing loss in a very large family with 25 affected individuals over 5 generations (Gürtler et al. 2005). In summary, based on the currently available information, it is unclear whether the R859Q variant is a pathogenic variant or a rare benign variant.
OMIM RCV000004787 SCV000024963 pathogenic Autosomal dominant nonsyndromic deafness 6 2008-09-01 no assertion criteria provided literature only

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