Variant summary: PPT1 c.674T>C (p.Phe225Ser) 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 4e-06 in 251426 control chromosomes (gnomAD). c.674T>C has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Mole_2001, Jilani_2019, Sangeeth_2019, Nouri_2021). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000310.4(PPT1):c.674T>C (p.Phe225Ser)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(5); Uncertain significance(1)
Pathogenic(1); Likely pathogenic(5); Uncertain significance(1)
7 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.674T>C (p.Phe225Ser)
Variation ID: 56211 Accession: VCV000056211.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40078612 (GRCh38) [ NCBI UCSC ] 1: 40544284 (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 Mar 22, 2025 Jul 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000310.4:c.674T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000301.1:p.Phe225Ser missense NM_001142604.2:c.365T>C NP_001136076.1:p.Phe122Ser missense NM_001363695.2:c.674T>C NP_001350624.1:p.Phe225Ser missense NC_000001.11:g.40078612A>G NC_000001.10:g.40544284A>G NG_009192.1:g.23859T>C LRG_690:g.23859T>C LRG_690t1:c.674T>C LRG_690p1:p.Phe225Ser - Protein change
- F122S, F225S
- Other names
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p.Phe225Ser
- Canonical SPDI
- NC_000001.11:40078611:A:G
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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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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 |
715 | 745 | |
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. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jun 3, 2024 | RCV000049622.10 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV003328554.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 11, 2021 | RCV001778693.2 |
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. |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 11, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002014863.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: PPT1 c.674T>C (p.Phe225Ser) 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.674T>C (p.Phe225Ser) 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 4e-06 in 251426 control chromosomes (gnomAD). c.674T>C has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Mole_2001, Jilani_2019, Sangeeth_2019, Nouri_2021). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: yes
Allele origin:
unknown
|
3billion, Medical Genetics
Accession: SCV004013871.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging … (more)
The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.95). The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with PPT1-related disorder (ClinVar ID: VCV000056211/PMID: 11589012). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11589012, 21990111, 31741823). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Neurodegeneration (present) , Rapidly progressive (present) , Blindness (present) , Visual loss (present) , Mental deterioration (present) , Cognitive impairment (present) , Memory impairment (present) , Abnormality of salivation (present) , Excessive salivation (present) , Strabismus (present) , Developmental regression (present) , Global developmental delay (present) , Growth delay (present) , Microcephaly (present) , Mild microcephaly (present) , Neck muscle weakness (present) , Sleep abnormality (present) , Late chronotype (present) , Sleep abnormality (present) , Sleep abnormality (present) , Circadian rhythm sleep disorder (present) , Dull (present) , Muscular atrophy (present) , Muscular dystrophy (present)
Zygosity: Homozygote
|
|
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Likely pathogenic
(Mar 13, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004035749.1
First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11589007, 11589012, 12125808, 14997939, 31741823, 34695666, Sangeeth_2019_Poster) (less)
|
|
|
Likely pathogenic
(Feb 14, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005052443.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Nov 06, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413530.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP3, PP4, PM2_moderate, PM3, PS4_moderate
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Jun 03, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002229838.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 225 of the PPT1 protein (p.Phe225Ser). … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 225 of the PPT1 protein (p.Phe225Ser). This variant is present in population databases (rs386833662, gnomAD 0.003%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 11589012, 31741823). ClinVar contains an entry for this variant (Variation ID: 56211). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
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Likely pathogenic
(Jul 01, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004704131.10
First in ClinVar: Mar 10, 2024 Last updated: Mar 22, 2025 |
Comment:
PPT1: PM3:Strong, PM1, PM2, PP3
Number of individuals with the variant: 3
|
|
|
probable-pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: not provided
|
Ceroid lipofuscinosis neuronal 1
Affected status: not provided
Allele origin:
not provided
|
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082029.1
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
|
Comment:
Converted during submission to Likely pathogenic.
|
Comment:
Comment:
The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.95). The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with PPT1-related disorder (ClinVar ID: VCV000056211/PMID: 11589012). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11589012, 21990111, 31741823). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11589007, 11589012, 12125808, 14997939, 31741823, 34695666, Sangeeth_2019_Poster)
Comment:
PP3, PP4, PM2_moderate, PM3, PS4_moderate
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 225 of the PPT1 protein (p.Phe225Ser). This variant is present in population databases (rs386833662, gnomAD 0.003%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 11589012, 31741823). ClinVar contains an entry for this variant (Variation ID: 56211). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
PPT1: PM3:Strong, PM1, PM2, PP3
Comment:
Converted during submission to Likely pathogenic.
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. |
Comment:
Variant summary: PPT1 c.674T>C (p.Phe225Ser) 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 4e-06 in 251426 control chromosomes (gnomAD). c.674T>C has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Mole_2001, Jilani_2019, Sangeeth_2019, Nouri_2021). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.95). The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with PPT1-related disorder (ClinVar ID: VCV000056211/PMID: 11589012). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11589012, 21990111, 31741823). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11589007, 11589012, 12125808, 14997939, 31741823, 34695666, Sangeeth_2019_Poster)
Comment:
PP3, PP4, PM2_moderate, PM3, PS4_moderate
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 225 of the PPT1 protein (p.Phe225Ser). This variant is present in population databases (rs386833662, gnomAD 0.003%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 11589012, 31741823). ClinVar contains an entry for this variant (Variation ID: 56211). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
PPT1: PM3:Strong, PM1, PM2, PP3
Comment:
Converted during submission to Likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and genetic profile of children with unexplained intellectual disability/developmental delay and epilepsy. | Nouri N | Epilepsy research | 2021 | PMID: 34695666 |
| High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses. | Jilani A | JIMD reports | 2019 | PMID: 31741823 |
| 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 |
| Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. | Mole SE | Neurogenetics | 2005 | PMID: 15965709 |
| The genetic spectrum of human neuronal ceroid-lipofuscinoses. | Mole SE | Brain pathology (Zurich, Switzerland) | 2004 | PMID: 14997939 |
| Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2). | Hofmann SL | Current molecular medicine | 2002 | PMID: 12125808 |
| New mutations in the neuronal ceroid lipofuscinosis genes. | Mole SE | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2001 | PMID: 11589012 |
| Infantile neuronal ceroid lipofuscinosis: no longer just a 'Finnish' disease. | Hofmann SL | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2001 | PMID: 11589007 |
| The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. | Bellizzi JJ 3rd | Proceedings of the National Academy of Sciences of the United States of America | 2000 | PMID: 10781062 |
Text-mined citations for rs386833662 ...
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 Apr 07, 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.