ClinVar Miner

Submissions for variant NM_020631.5(PLEKHG5):c.440-2A>G (rs144750655)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485207 SCV000573584 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing A variant of uncertain significance have been identified in the PLEKGH5 gene. The c.440-2A>G variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 6. It is predicted to cause abnormal gene splicing, either leading to 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. The c.440-2A>G variant is observed in 40/125664 (0.03%) alleles in individuals of European background. (Lek et al., 2016). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000705445 SCV000834442 likely pathogenic Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2019-11-14 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the PLEKHG5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs144750655, ExAC 0.03%). This variant has not been reported in the literature in individuals with PLEKHG5-related disease. ClinVar contains an entry for this variant (Variation ID: 423836). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PLEKHG5 are known to be pathogenic (PMID: 17564964, 23777631). 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.
Fulgent Genetics,Fulgent Genetics RCV000705445 SCV000893401 likely pathogenic Distal spinal muscular atrophy, autosomal recessive 4; Charcot-Marie-Tooth disease, recessive intermediate c 2018-10-31 criteria provided, single submitter clinical testing

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