ClinVar Miner

Submissions for variant NM_015404.4(WHRN):c.2027C>G (p.Pro676Arg) (rs139279977)

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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 RCV000216709 SCV000271633 uncertain significance not specified 2015-09-03 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Pro676Arg var iant in DFNB31 has not been previously reported in individuals with hearing loss , but has been identified in 0.24 % (159/66274) of European chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs139279977). 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 a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Pro676Arg variant is uncertain, its frequency in the general population suggests that it i s more likely to be benign.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000216709 SCV000297258 uncertain significance not specified 2015-11-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000185564 SCV000476746 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 RCV000185565 SCV000476747 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415812 SCV000493636 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing
Invitae RCV000415812 SCV001208849 uncertain significance not provided 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 676 of the WHRN protein (p.Pro676Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs139279977, 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: 203387). 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: "Possibly 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.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185564 SCV000238455 uncertain significance Usher syndrome, type 2D 2015-02-03 no assertion criteria provided research This variant (NM_015404.3:c.2027C>G;p.P676R) is considered a variant of uncertain significance, as it has not been reported in the literature; however, it is seen in 172 out of 12,2058 alleles in ExAC with no homozygotes. The amino acid is not in a functional domain.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185565 SCV000238456 uncertain significance Deafness, autosomal recessive 31 2015-02-03 no assertion criteria provided research This variant (NM_015404.3:c.2027C>G;p.P676R) is considered a variant of uncertain significance, as it has not been reported in the literature; however, it is seen in 172 out of 12,2058 alleles in ExAC with no homozygotes. The amino acid is not in a functional domain.

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