ClinVar Miner

Submissions for variant NM_015404.4(WHRN):c.1349G>A (p.Arg450His) (rs200377723)

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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 RCV000038866 SCV000062544 uncertain significance not specified 2015-07-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg450His var iant in DFNB31 has been identified by our laboratory in 1 individual with sensor ineural hearing loss but a second DFNB31 variant has not been identified. This v ariant has also been identified in 0.2% (19/8644) of East Asian chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2 00377723). Arginine (Arg) at position 450 is not conserved in mammals or evoluti onarily distant species. Of note, horse has a histidine (His) at this position, raising the possibility that this change may be tolerated. Additional computati onal prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg450His vari ant is uncertain, its frequency in the general population and conservation data suggest that it is more likely to be benign.
Illumina Clinical Services Laboratory,Illumina RCV001168063 SCV001330621 uncertain significance Usher syndrome, type 2D 2018-01-12 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 RCV001168064 SCV001330622 uncertain significance Deafness, autosomal recessive 31 2018-01-12 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.
Invitae RCV001206517 SCV001377828 uncertain significance not provided 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 450 of the WHRN protein (p.Arg450His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs200377723, ExAC 0.2%). This variant has not been reported in the literature in individuals with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 45648). 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: "Deleterious"; PolyPhen-2: "Benign"; 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.

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