Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV000344678 | SCV000363905 | uncertain significance | Usher syndrome type 1D | 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 Laboratory Services, |
RCV000391639 | SCV000363906 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 12 | 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001797703 | SCV002041767 | uncertain significance | not specified | 2021-11-04 | criteria provided, single submitter | clinical testing | Variant summary: CDH23 c.8878G>A (p.Val2960Ile) results in a conservative amino acid change located in the last cadherin repeat domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 246918 control chromosomes (gnomAD). This frequency is not higher than the maximum expected for a pathogenic variant in CDH23 causing Usher Syndrome (0.0032), allowing no conclusion about variant significance. The variant, c.8878G>A, has been reported in the literature in a compound heterozygous individual affected with retinal disease and mild hearing loss (i.e. suspected Usher Syndrome), who carried another (VUS) missense variant in trans (Zhao_2015). This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Invitae | RCV002520622 | SCV003499384 | uncertain significance | not provided | 2022-02-08 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2960 of the CDH23 protein (p.Val2960Ile). This variant is present in population databases (rs748152139, gnomAD 0.006%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 25472526). ClinVar contains an entry for this variant (Variation ID: 300466). 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: "Not Available"; 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. |