ClinVar Miner

Submissions for variant NM_000310.3(PPT1):c.541G>T (p.Val181Leu) (rs148412181)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049613 SCV000485419 likely pathogenic Neuronal ceroid lipofuscinosis 1 2015-12-09 criteria provided, single submitter clinical testing
GeneDx RCV000436288 SCV000520956 likely pathogenic not provided 2017-01-30 criteria provided, single submitter clinical testing The V181L variant in the PPT1 gene has been reported previously in association with late-infantile and juvenile neuronal ceroid lipofuscinosis when present in the homozygous state or when in trans with another disease-causing variant (Mole et al., 2009; Simonati et al., 2009; Pérez-Poyato et al., 2011). The V181L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V181L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The V181L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000049613 SCV001211250 pathogenic Neuronal ceroid lipofuscinosis 1 2019-04-04 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 181 of the PPT1 protein (p.Val181Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs148412181, ExAC no frequency). This variant has been observed in several individuals affected with neuronal ceroid lipofuscinosis (NCL) and segregated with NCL in affected families (PMID: 21499717, 10477428, 19302939). ClinVar contains an entry for this variant (Variation ID: 56202). This variant has been reported to affect PPT1 protein function (PMID: 28878621). This variant disrupts the p.Val181 amino acid residue in PPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22387303, 23374165, 28878621, 9664077, 11440996). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049613 SCV000082020 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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