ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.169dup (p.Met57fs)

dbSNP: rs386833634
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049593 SCV000220573 likely pathogenic Neuronal ceroid lipofuscinosis 1 2014-08-03 criteria provided, single submitter literature only
Invitae RCV000049593 SCV000284561 pathogenic Neuronal ceroid lipofuscinosis 1 2021-10-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met57Asnfs*45) in the PPT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This premature translational stop signal has been observed in individuals with infantile neuronal ceroid lipofuscinosis (PMID: 9571187, 10679943, 21990111). This variant is also known as 169 (A169i) and as c.162-163insA. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001009045 SCV001168855 pathogenic not provided 2021-06-24 criteria provided, single submitter clinical testing Reported as c.169-170insA by Waliany et al. (2000) using alternate nomenclature; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10679943, 9571187, 21990111, 28878621, 10649502, 26707855, 27535533)
CeGaT Center for Human Genetics Tuebingen RCV001009045 SCV001246700 pathogenic not provided 2017-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000584447 SCV001361118 pathogenic Neuronal ceroid lipofuscinosis 2020-12-21 criteria provided, single submitter clinical testing Variant summary: PPT1 c.169dupA (p.Met57AsnfsX45) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251438 control chromosomes (gnomAD). c.169dupA has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Santorelli_1998, Waliany_2000, Levin_2014). These data indicate that the variant is likely to be associated with disease. Two publications report experimental evidence demonstrating an effect of the variant on the expression of other genes via whole transcriptome profiling (Tikka_2016, Pezzini_2017). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049593 SCV000082000 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000584447 SCV000692329 pathogenic Neuronal ceroid lipofuscinosis 2008-09-22 no assertion criteria provided clinical testing
Natera, Inc. RCV000049593 SCV001453964 pathogenic Neuronal ceroid lipofuscinosis 1 2020-09-16 no assertion criteria provided clinical testing

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