ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.727-2A>T

dbSNP: rs386833664
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224164 SCV000281082 pathogenic not provided 2016-03-28 criteria provided, single submitter clinical testing
GeneDx RCV000224164 SCV000568387 likely pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing A c.727-2 A>T variant that is likely pathogenic has been identified in the PPT1 gene. The c.727-2 A>T variant was previously reported in one patient with infantile neuronal ceroid lipofuscinoses, with known palmitoyl-protein thioesterase deficiency, who also harbored a second PPT1 pathogenic variant, however phase was not reported (Das et al., 1998). The c.727-2 A>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.727-2 A>T splice site variant gene destroys the canonical splice acceptor site in intron 7. 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. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000049624 SCV001421942 pathogenic Neuronal ceroid lipofuscinosis 1 2023-08-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the PPT1 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 PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs386833664, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077). This variant is also known as T (IVS7, -2). ClinVar contains an entry for this variant (Variation ID: 56213). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049624 SCV000082031 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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