ClinVar Miner

Submissions for variant NM_015404.4(WHRN):c.139A>G (p.Thr47Ala) (rs556585167)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000613409 SCV000731623 uncertain significance not specified 2017-05-22 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr47Ala vari ant in DFNB31 has not been previously reported in individuals with hearing loss, but was identified in 0.2% (36/18528) of East Asian chromosomes by the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs556585167 ). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In s ummary, while the clinical significance of the p.Thr47Ala variant is uncertain, its frequency suggests that it is more likely to be benign.
Invitae RCV001067423 SCV001232485 uncertain significance not provided 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 47 of the WHRN protein (p.Thr47Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs556585167, ExAC 0.1%). This variant has not been reported in the literature in individuals with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 517373). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV001168205 SCV001330781 uncertain significance Usher syndrome, type 2D 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001168206 SCV001330782 uncertain significance Deafness, autosomal recessive 31 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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