ClinVar Miner

Submissions for variant NM_000310.3(PPT1):c.169dup (p.Met57fs) (rs386833634)

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Total submissions: 7
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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 2019-11-14 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. This variant has been reported in the literature in individuals affected with infantile neuronal ceroid lipofuscinosis (PMID: 9571187, 21990111, 10679943). This variant is also known as 169 (A169i) and as c.162-163insA in the literature. ClinVar contains an entry for this variant (Variation ID: 56182). Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001009045 SCV001168855 pathogenic not provided 2018-09-13 criteria provided, single submitter clinical testing The c.169dupA variant in the PPT1 gene has been reported previously in the homozygous state or with a second PPT1 variant in patients with infantile neuronal ceroid lipofuscinosis (Santorelli et al., 1998; Waliany et al., 2000). This variant causes a frameshift starting with codon Methionine 57, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 45 of the new reading frame, denoted p.Met57AsnfsX45. The c.169dupA variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.169dupA as a pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001009045 SCV001246700 pathogenic not provided 2017-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049593 SCV001361118 pathogenic Neuronal ceroid lipofuscinosis 1 2019-06-07 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. 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 may 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). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified 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

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