Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000521965 | SCV000621178 | likely pathogenic | not provided | 2017-09-29 | criteria provided, single submitter | clinical testing | A variant that is likely pathogenic was identified in the ALMS1 gene. The c.1435+2_1435+15del14 variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). In silico splice prediction algorithms suggest that the c.1435+2_1435+15del14 variant may result in the loss of the natural splice donor site, which could lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. |
Counsyl | RCV000672935 | SCV000798091 | likely pathogenic | Alstrom syndrome | 2018-02-22 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000672935 | SCV001575198 | likely pathogenic | Alstrom syndrome | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change affects a splice site in intron 7 of the ALMS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452373). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Ambry Genetics | RCV002395256 | SCV002699286 | likely pathogenic | Cardiovascular phenotype | 2022-02-17 | criteria provided, single submitter | clinical testing | The c.1435+2_1435+15del14 intronic variant results from a deletion of 14 nucleotides between positions c.1435+2 and c.1435+15 and involves the canonical splice donor site after coding exon 7of the ALMS1 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). The canonical splice donor site is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, the exact impact of this deletion on ALMS1 splicing and function is currently unknown. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. |
Natera, |
RCV000672935 | SCV002080413 | likely pathogenic | Alstrom syndrome | 2021-09-30 | no assertion criteria provided | clinical testing |