ClinVar Genomic variation as it relates to human health
NM_000310.4(PPT1):c.329A>G (p.Asn110Ser)
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(1); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000310.4(PPT1):c.329A>G (p.Asn110Ser)
Variation ID: 196249 Accession: VCV000196249.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40092078 (GRCh38) [ NCBI UCSC ] 1: 40557750 (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 Mar 8, 2017 May 1, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000310.4:c.329A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000301.1:p.Asn110Ser missense NM_001142604.2:c.125-2566A>G intron variant NM_001363695.2:c.329A>G NP_001350624.1:p.Asn110Ser missense NC_000001.11:g.40092078T>C NC_000001.10:g.40557750T>C NG_009192.1:g.10393A>G LRG_690:g.10393A>G LRG_690t1:c.329A>G LRG_690p1:p.Asn110Ser - Protein change
- N110S
- Other names
- p.N110S:AAT>AGT
- Canonical SPDI
- NC_000001.11:40092077:T:C
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Exome Aggregation Consortium (ExAC) 0.00018
The Genome Aggregation Database (gnomAD), exomes 0.00019
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 | ||
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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
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
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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 (5) |
criteria provided, conflicting classifications
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Jan 27, 2024 | RCV000625813.14 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2023 | RCV000724058.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 8, 2021 | RCV002516724.3 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 1, 2019 | RCV001252359.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 26, 2023 | RCV003235097.3 |
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
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. |
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Uncertain significance
(Dec 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 1
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746371.1
First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018 |
Age: 10-19 weeks gestation
Geographic origin: Iran
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Uncertain significance
(Aug 22, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000228845.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Apr 01, 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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002791947.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Aug 04, 2023)
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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: SCV000242336.14
First in ClinVar: Aug 07, 2015 Last updated: Aug 13, 2023 |
Comment:
Reported in the heterozygous state in a patient with cognitive impairment, ADHD, and epilepsy in the published literature; however, a second PPT1 variant was not … (more)
Reported in the heterozygous state in a patient with cognitive impairment, ADHD, and epilepsy in the published literature; however, a second PPT1 variant was not identified (Atli et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a homozygous state in a patient with episodic torticollis and sudden cardiac arrest who also harbored another homozygous variant in a gene related to the phenotype (Ozturk et al., 2022); This variant is associated with the following publications: (PMID: 30541466, 33528079, 34426522, 35693655) (less)
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Uncertain significance
(Oct 13, 2021)
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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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Revvity Omics, Revvity
Accession: SCV003809831.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934442.2
First in ClinVar: Jun 24, 2023 Last updated: Feb 04, 2024 |
Comment:
Variant summary: PPT1 c.329A>G (p.Asn110Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: PPT1 c.329A>G (p.Asn110Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251452 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PPT1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00019 vs 0.0014), allowing no conclusion about variant significance. c.329A>G has been reported in the literature in the homozygous state in an individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) who had significantly reduced PPT1 enzyme activity compared to normal controls (Sheth_2018). These data indicate that the variant may be associated with disease. However, it has also been reported in the homozygous state in an individual from a consanguineous family, affected with Childhood Onset Neurodegeneration with Ataxia and Seizures, who had a normal PPT1 level and was also homozygous for a variant in the ADPRHL2 gene (c.235A>C, p.T79P) which may explain the phenotype (Ozturk_2022). Finally, the variant has also been reported as a heterozygous genotype in an individual affected with cognitive impairment, ADHD, and epilepsy (Atli_2022). Thus, these reports do not allow for any strong conclusions to be made about variant significance. The following publications have been ascertained in the context of this evaluation (PMID: 33528079, 30541466, 35693655). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=7) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Pathogenic
(Jan 27, 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: SCV000818289.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 110 of the PPT1 protein (p.Asn110Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 110 of the PPT1 protein (p.Asn110Ser). This variant is present in population databases (rs142894102, gnomAD 0.06%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 30541466). ClinVar contains an entry for this variant (Variation ID: 196249). 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 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Jul 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003748459.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.329A>G (p.N110S) alteration is located in exon 3 (coding exon 3) of the PPT1 gene. This alteration results from a A to G substitution … (more)
The c.329A>G (p.N110S) alteration is located in exon 3 (coding exon 3) of the PPT1 gene. This alteration results from a A to G substitution at nucleotide position 329, causing the asparagine (N) at amino acid position 110 to be replaced by a serine (S). The in silico prediction for the p.N110S alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jan 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
unknown
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001428113.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
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Uncertain significance
(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: SCV001464023.1
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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Stress-induced Childhood Onset Neurodegeneration with Ataxia and Seizures (CONDSIAS) Presenting with Torticollis Attacks: Phenotypic Variability of the Same Mutation in Two Turkish Patients. | Ozturk G | Annals of Indian Academy of Neurology | 2022 | PMID: 35693655 |
Customised targeted massively parallel sequencing enables more precise diagnosis of patients with epilepsy. | Atli EI | Internal medicine journal | 2022 | PMID: 33528079 |
Batten disease: biochemical and molecular characterization revealing novel PPT1 and TPP1 gene mutations in Indian patients. | Sheth J | BMC neurology | 2018 | PMID: 30541466 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PPT1 | - | - | - | - |
Text-mined citations for rs142894102 ...
HelpRecord last updated May 01, 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.