ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.376+1G>T (rs746053679)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000522524 SCV000856581 likely pathogenic not provided 2017-08-23 criteria provided, single submitter clinical testing
GeneDx RCV000522524 SCV000617490 pathogenic not provided 2015-11-11 criteria provided, single submitter clinical testing The c.376+1G>T pathogenic variant in the SPG7 gene has been reported previously in one individual with hereditary spastic paraparesis who also harbored a pathogenic missense variant, although the phase of these two variants was not confirmed (Klebe et al., 2012). This splice site variant destroys the canonical splice donor site in intron 3. 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.376+1G>T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.376+1G>T as a pathogenic variant.
Invitae RCV000467232 SCV000552960 likely pathogenic Spastic paraplegia 7 2016-10-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the SPG7 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 (rs746053679, ExAC 0.003%). This variant has been reported in the literature in one individual affected with hereditary spastic paraplegia (PMID: 23065789). In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in SPG7 are known to be pathogenic (PMID: 22964162). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.

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