ClinVar Genomic variation as it relates to human health
NM_000310.4(PPT1):c.169dup (p.Met57fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000310.4(PPT1):c.169dup (p.Met57fs)
Variation ID: 56182 Accession: VCV000056182.38
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40092462-40092463 (GRCh38) [ NCBI UCSC ] 1: 40558134-40558135 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 24, 2013 May 12, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000310.4:c.169dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000301.1:p.Met57fs frameshift NM_000310.3:c.169dupA NM_001142604.2:c.125-2951dup intron variant NM_001363695.2:c.169dup NP_001350624.1:p.Met57fs frameshift NC_000001.11:g.40092469dup NC_000001.10:g.40558141dup NG_009192.1:g.10008dup LRG_690:g.10008dup LRG_690t1:c.169dup LRG_690p1:p.Met57fs - Protein change
- M57fs
- Other names
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- Canonical SPDI
- NC_000001.11:40092462:TTTTTTT:TTTTTTTT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PPT1 | - | - |
GRCh38 GRCh37 |
687 | 715 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000049593.18 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 21, 2020 | RCV000584447.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 24, 2021 | RCV001009045.19 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361118.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 09, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jun 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001168855.2
First in ClinVar: Mar 16, 2020 Last updated: Sep 26, 2021 |
Comment:
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 … (more)
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) (less)
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Likely pathogenic
(Aug 03, 2014)
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criteria provided, single submitter
Method: literature only
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Ceroid lipofuscinosis neuronal 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220573.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Jul 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 1
Affected status: yes
Allele origin:
maternal
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921784.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0102 - Loss of function is a known mechanism of disease in this gene and is associated with neuronal ceroid lipofuscinosis 1 (MIM#256730). (I) 0106 … (more)
0102 - Loss of function is a known mechanism of disease in this gene and is associated with neuronal ceroid lipofuscinosis 1 (MIM#256730). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (SP) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and have been observed in individuals with neuronal ceroid lipofuscinosis (ClinVar, Decipher). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic in individuals with neuronal ceroid lipofuscinosis (ClinVar). (SP) 1201 - Heterozygous variant detected likely in trans with a second pathogenic heterozygous variant (p.(Arg151*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004204147.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000284561.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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 variant is present in population databases (rs386833634, gnomAD 0.006%). 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. ClinVar contains an entry for this variant (Variation ID: 56182). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246700.21
First in ClinVar: May 09, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 17, 1998)
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no assertion criteria provided
Method: literature only
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CEROID LIPOFUSCINOSIS, NEURONAL, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029674.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a 4-year-old boy with infantile-onset CLN1 (256730), Santorelli et al. (1998) identified a single adenine insertion at nucleotide position 169 (160insA) in the PPT … (more)
In a 4-year-old boy with infantile-onset CLN1 (256730), Santorelli et al. (1998) identified a single adenine insertion at nucleotide position 169 (160insA) in the PPT gene. The mutation was homozygous in the proband, heterozygous in his healthy parents, and not found in control alleles. The mutation led to an early stop codon, resulting in an abnormal and truncated PPT protein. The 4-year-old boy developed normally until the age of 12 months. He could sit and crawl; however, he never achieved independent walking. Psychomotor regression occurred over the subsequent 2 months. At age 14 months, he had lost most of his motor abilities and showed a progressive worsening of his clinical status. At approximately 18 months of age, he was hypotonic and also presented severe speech impairment, visual loss, and myoclonic seizures. Electroretinogram and visual evoked potentials were altered. MRI showed severe cerebral cortical atrophy with relative sparing of the cerebellum. Ultrastructural studies showed recurrent granular osmiophilic deposits in both endothelial cells and fibroblasts on skin biopsy. (less)
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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Ceroid lipofuscinosis neuronal 1
Affected status: not provided
Allele origin:
not provided
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082000.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
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Comment:
Converted during submission to Likely pathogenic.
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Pathogenic
(Sep 22, 2008)
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no assertion criteria provided
Method: clinical testing
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Neuronal ceroid lipofuscinosis
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692329.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453964.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells. | Pezzini F | Frontiers in molecular neuroscience | 2017 | PMID: 28878621 |
Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules. | Tikka S | Neuromolecular medicine | 2016 | PMID: 26707855 |
Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. | Levin SW | The Lancet. Neurology | 2014 | PMID: 24997880 |
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. | Kousi M | Human mutation | 2012 | PMID: 21990111 |
Detection of eight novel palmitoyl protein thioesterase (PPT) mutations underlying infantile neuronal ceroid lipofuscinosis (INCL;CLN1). | Salonen T | Human mutation | 2000 | PMID: 10679943 |
Identification of three novel mutations of the palmitoyl-protein thioesterase-1 (PPT1) gene in children with neuronal ceroid-lipofuscinosis. | Waliany S | Human mutation | 2000 | PMID: 10649502 |
A novel insertion mutation (A169i) in the CLN1 gene is associated with infantile neuronal ceroid lipofuscinosis in an Italian patient. | Santorelli FM | Biochemical and biophysical research communications | 1998 | PMID: 9571187 |
Text-mined citations for rs386833634 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.