The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). The variant is in trans with the other variant (NM_000310.4:c.433+1G>A). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.29). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PPT1-related disorder (PMID: 21990111). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_000310.4(PPT1):c.413C>T (p.Ser138Leu)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
5 out of 8 submissions contributed to this classification
Help
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.
8
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000310.4(PPT1):c.413C>T (p.Ser138Leu)
Variation ID: 56194 Accession: VCV000056194.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.2 1: 40091349 (GRCh38) [ NCBI UCSC ] 1: 40557021 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 5, 2025 Jun 9, 2025 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000310.4:c.413C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000301.1:p.Ser138Leu missense NM_001142604.2:c.125-1837C>T intron variant NM_001363695.2:c.413C>T NP_001350624.1:p.Ser138Leu missense NC_000001.11:g.40091349G>A NC_000001.10:g.40557021G>A NG_009192.1:g.11122C>T LRG_690:g.11122C>T LRG_690t1:c.413C>T LRG_690p1:p.Ser138Leu P50897:p.Ser138Leu - Protein change
- S138L
- Other names
- -
- Canonical SPDI
- NC_000001.11:40091348:G:A
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| PPT1 | Gene associated with autosomal recessive phenotype | No evidence available |
GRCh38 GRCh37 |
752 | 786 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 2, 2025 | RCV000049605.18 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 9, 2025 | RCV003226183.2 |
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. |
Expand all rows
Collapse all rows
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 04, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis 1 |
Mendelics
Accession: SCV002518902.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Sep 01, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis 1 |
3billion
Accession: SCV002573094.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
show
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). The variant is in trans with the other variant (NM_000310.4:c.433+1G>A). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.29). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PPT1-related disorder (PMID: 21990111). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Primary microcephaly (present) , Global developmental delay (present)
Zygosity: Single Heterozygote
Platform type: whole exome sequencing
Platform name: NovaSeq
|
|
|
Likely pathogenic
(Feb 24, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis 1 |
Baylor Genetics
Accession: SCV004204136.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jun 09, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922624.2
First in ClinVar: May 13, 2023 Last updated: Jul 05, 2025 |
Comment:
show
Variant summary: PPT1 c.413C>T (p.Ser138Leu) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes.c.413C>T has been reported in the literature in multiple individuals affected with rett syndrome, neurodevelopmental disabilities, progressive myoclonic epilepsy and epilepsy (example: Iwama_2019, Kim_2019, Zhang_2020 and Zhao_2022). The following publications have been ascertained in the context of this evaluation (PMID: 21990111, 30842224, 30952489, 35217970). ClinVar contains an entry for this variant (Variation ID: 56194). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Feb 02, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neuronal ceroid lipofuscinosis 1 |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001208999.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025 |
Comment:
show
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 138 of the PPT1 protein (p.Ser138Leu). This variant is present in population databases (rs386833646, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis 1 (PMID: 21990111, 30842224; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56194). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PPT1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Aug 14, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Neuronal ceroid lipofuscinosis 1 |
Natera, Inc.
Accession: SCV002085995.2
First in ClinVar: Apr 23, 2022 Last updated: Jun 08, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Ceroid lipofuscinosis neuronal 1 |
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082012.2
First in ClinVar: Jul 24, 2013 Last updated: Jun 08, 2025
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
|
Observation: 1
Collection method: not provided
Allele origin: unknown
Affected status: not provided
Observation 1
Collection method: not provided
Allele origin: unknown
Affected status: not provided
|
|
|
Uncertain significance
(May 18, 2018)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Neuronal ceroid lipofuscinosis 1 |
Counsyl
Accession: SCV000800709.2
First in ClinVar: Jul 24, 2013 Last updated: Jun 29, 2025 |
Comment:
show
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
Comment:
Comment:
Variant summary: PPT1 c.413C>T (p.Ser138Leu) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes.c.413C>T has been reported in the literature in multiple individuals affected with rett syndrome, neurodevelopmental disabilities, progressive myoclonic epilepsy and epilepsy (example: Iwama_2019, Kim_2019, Zhang_2020 and Zhao_2022). The following publications have been ascertained in the context of this evaluation (PMID: 21990111, 30842224, 30952489, 35217970). ClinVar contains an entry for this variant (Variation ID: 56194). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 138 of the PPT1 protein (p.Ser138Leu). This variant is present in population databases (rs386833646, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis 1 (PMID: 21990111, 30842224; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56194). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PPT1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
Converted during submission from probable-pathogenic to Likely pathogenic.
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic analysis and identification of novel variations in Chinese patients with pediatric epilepsy by whole-exome sequencing. | Zhao X | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2022 | PMID: 35217970 |
| Proband-Only Clinical Exome Sequencing for Neurodevelopmental Disabilities. | Kim SH | Pediatric neurology | 2019 | PMID: 30952489 |
| Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing. | Iwama K | Journal of medical genetics | 2019 | PMID: 30842224 |
| 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 |
Text-mined citations for rs386833646 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jul 05, 2025
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.