ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.1432+2_1432+15del (rs1203193062)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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 2020-02-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the ALMS1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452373). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). 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.

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