ClinVar Miner

Submissions for variant NM_004999.4(MYO6):c.3137+1G>A

dbSNP: rs200713129
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002308912 SCV002601173 uncertain significance not provided 2022-10-27 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV002308912 SCV002941404 likely pathogenic not provided 2023-12-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 29 of the MYO6 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 MYO6 are known to be pathogenic (PMID: 12687499, 18348273, 23767834, 25999546, 30582396). This variant is present in population databases (rs200713129, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYO6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1723638). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
PreventionGenetics, part of Exact Sciences RCV004534048 SCV004114109 uncertain significance MYO6-related disorder 2023-01-19 criteria provided, single submitter clinical testing The MYO6 c.3137+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. The disruption of this splice donor site may lead to an exon skipping and result in an in-frame deletion of ten amino acids, however no mRNA studies are available to evaluate the actual effect of this variant. This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-76604978-G-A) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1723638/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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