Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000442415 | SCV000521054 | pathogenic | not provided | 2022-05-13 | criteria provided, single submitter | clinical testing | Published cDNA study in an affected individual demonstrates that variant leads to abnormal gene splicing and a loss of the first 52 base pairs in exon 9 in half of the transcripts, ultimately leading to a frameshift and replacement of the last 133 amino acids with 7 incorrect amino acids (Brenner et al., 2011); Not observed in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing.; This variant is associated with the following publications: (PMID: 29115496, 29986705, 21438779, 31706454) |
| Genetic Testing Center for Deafness, |
RCV001290159 | SCV001478216 | pathogenic | Waardenburg syndrome type 2A | 2019-01-01 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV001290159 | SCV001524571 | likely pathogenic | Waardenburg syndrome type 2A | 2019-08-08 | criteria provided, single submitter | clinical testing | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported to segregate with Waardenburg syndrome in a large family in which affected individuals had hearing loss and variable expression of premature graying [PMID: 21438779] Sequencing of c.909 G>A variant cDNA extracted from an affected individual demonstrated a loss of the first 52 base pairs in exon 9 in half of the transcripts [PMID: 21438779] |
| Labcorp Genetics |
RCV003766234 | SCV004569656 | pathogenic | Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8 | 2023-07-12 | criteria provided, single submitter | clinical testing | This variant has been observed in individuals with autosomal dominant Waardenburg syndrome (PMID: 21438779, 29115496). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 303 of the MITF mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MITF protein. This variant is also known as c.1212G>A. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 381604). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003987532 | SCV004804234 | pathogenic | Waardenburg syndrome type 2 | 2024-01-08 | criteria provided, single submitter | clinical testing | Variant summary: MITF c.909G>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' splice acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Brenner_2011). The variant was absent in 251358 control chromosomes (gnomAD). c.909G>A has been reported in the literature in multiple individuals affected with Waardenburg Syndrome with evidence of cosegregation with disease (Brenner_2011). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 21438779). ClinVar contains an entry for this variant (Variation ID: 381604). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Clinical Genetics Laboratory, |
RCV000442415 | SCV005196738 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing |