ClinVar Genomic variation as it relates to human health
NM_000310.4(PPT1):c.413C>T (p.Ser138Leu)
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.
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000310.4(PPT1):c.413C>T (p.Ser138Leu)
Variation ID: 56194 Accession: VCV000056194.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40091349 (GRCh38) [ NCBI UCSC ] 1: 40557021 (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 Feb 14, 2024 Dec 18, 2023 - HGVS
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Nucleotide 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
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- Canonical SPDI
- NC_000001.11:40091348:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00007
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
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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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Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Dec 18, 2023 | RCV000049605.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2023 | RCV003226183.1 |
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
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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
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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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Likely pathogenic
(Sep 20, 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: SCV004204136.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 18, 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:
germline
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Invitae
Accession: SCV001208999.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
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). … (more)
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; Invitae). 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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)
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Uncertain significance
(May 18, 2018)
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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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Counsyl
Accession: SCV000800709.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013 |
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Pathogenic
(May 04, 2022)
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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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Mendelics
Accession: SCV002518902.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573094.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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)
Clinical Features:
Primary microcephaly (present) , Global developmental delay (present)
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Pathogenic
(Mar 20, 2023)
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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: SCV003922624.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: PPT1 c.413C>T (p.Ser138Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: PPT1 c.413C>T (p.Ser138Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes (gnomAD). 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). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (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: SCV000082012.1
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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Uncertain significance
(Feb 05, 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: SCV002085995.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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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 ...
HelpRecord last updated Feb 20, 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.