Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
UW Hindbrain Malformation Research Program, |
RCV000201689 | SCV000256261 | pathogenic | Joubert syndrome 3 | 2015-02-23 | criteria provided, single submitter | research | |
Invitae | RCV001226946 | SCV001399278 | pathogenic | Familial aplasia of the vermis | 2024-01-05 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Thr304Asnfs*6) in the AHI1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AHI1 are known to be pathogenic (PMID: 15322546, 16453322, 28442542, 29186038). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 16453322, 28431631). This variant is also known as c.903insA and c.903_910insA. ClinVar contains an entry for this variant (Variation ID: 217536). For these reasons, this variant has been classified as Pathogenic. |
Breda Genetics srl | RCV000201689 | SCV001422498 | pathogenic | Joubert syndrome 3 | 2020-07-15 | criteria provided, single submitter | clinical testing | The variant c.910dupA (p.Thr304Asnfs*6) is reported as pathogenic for Joubert syndrome 3 in ClinVar (Variation ID: 217536). The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 6 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is present in gnomAD with an estimated allele frequency of 0.0001588, with no homozygous individuals reported. However, this variant was filtered out the gnomAD database because of it is found in a low complexity region and failed the random forest filters, due to presence of a poli-T stretch. Chafai-Elalaoui et al. (2015) reported the pathogenic variant c.910dupA (p.Thr304Asnfs*6) in the homozygous state in 3 affected sibling of a Moroccan family with Joubert syndrome (PMID: 26541515). The same mutation had already been reported by Kroes et al. (2008) in two Dutch patients in the compound heterozygous state (PMID: 18054307). |
Institute of Human Genetics, |
RCV000201689 | SCV001443009 | pathogenic | Joubert syndrome 3 | 2020-03-01 | criteria provided, single submitter | clinical testing | Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2,PM3 |
Gene |
RCV002288819 | SCV002578458 | pathogenic | not provided | 2022-10-04 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29186038, 28442542, 15322546, 26541515, 28431631, 33691693, 29974258, 26092869, 16453322) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002469063 | SCV002766400 | pathogenic | Joubert syndrome and related disorders | 2022-11-25 | criteria provided, single submitter | clinical testing | Variant summary: AHI1 c.910dupA (p.Thr304AsnfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 147308 control chromosomes (gnomAD, v3.1). c.910dupA has been reported in the literature as a biallelic genotype in multiple individuals affected with Joubert Syndrome And Related Disorders (e.g. Valente_2006, Chafai-Elalaoui_2015). These data indicate that the variant is very likely to be associated with disease. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Fulgent Genetics, |
RCV000201689 | SCV002810152 | pathogenic | Joubert syndrome 3 | 2021-12-19 | criteria provided, single submitter | clinical testing |