ClinVar Miner

Submissions for variant NM_153676.4(USH1C):c.790G>A (p.Val264Ile) (rs79875849)

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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 RCV000403884 SCV000369505 uncertain significance Nonsyndromic Hearing Loss, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000310482 SCV000369506 uncertain significance Usher syndrome, type 1C 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825027 SCV000966224 likely benign not specified 2018-03-09 criteria provided, single submitter clinical testing p.Val264Ile in exon 10 of USH1C: This variant is classified as likely benign due to a lack of conservation across species, including mammals. Of note, >40 mamma ls have a Isoleucine (Ile) at this position despite high nearby amino acid conse rvation. In addition, computational prediction tools do not suggest a high likel ihood of impact to the protein. ACMG/AMP Criteria applied:BP4_Strong.
Invitae RCV001068380 SCV001233490 uncertain significance not provided 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 264 of the USH1C protein (p.Val264Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs79875849, ExAC 0.02%). This variant has not been reported in the literature in individuals with USH1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 303809). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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