A Homozygote Missense variant c.713C>T in Exon 7 of the PPT1 gene that results in the amino acid substitution p.Pro238Leu was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic(Variant ID 236407). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
ClinVar Genomic variation as it relates to human health
NM_000310.4(PPT1):c.713C>T (p.Pro238Leu)
Germline
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.
(7)
Help
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/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000310.4(PPT1):c.713C>T (p.Pro238Leu)
Variation ID: 236407 Accession: VCV000236407.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40078573 (GRCh38) [ NCBI UCSC ] 1: 40544245 (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 Jun 25, 2016 Jul 23, 2024 Dec 21, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000310.4:c.713C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000301.1:p.Pro238Leu missense NM_001142604.2:c.404C>T NP_001136076.1:p.Pro135Leu missense NM_001363695.2:c.713C>T NP_001350624.1:p.Pro238Leu missense NC_000001.11:g.40078573G>A NC_000001.10:g.40544245G>A NG_009192.1:g.23898C>T LRG_690:g.23898C>T LRG_690t1:c.713C>T LRG_690p1:p.Pro238Leu - Protein change
- P238L, P135L
- Other names
- -
- Canonical SPDI
- NC_000001.11:40078572: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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effect on protein activity; Variation Ontology [ VariO:0053]Significantly reduced activity of PPT1 enzyme [submitted by Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics]
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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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- 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. |
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| PPT1 | - | - |
GRCh38 GRCh37 |
695 | 723 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 8, 2023 | RCV000225555.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 21, 2023 | RCV004594031.1 |
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
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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|---|---|---|---|---|---|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Suma Genomics
Accession: SCV001847688.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002053786.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
|
|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003922038.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
A Homozygote Missense variant c.713C>T in Exon 7 of the PPT1 gene that results in the amino acid substitution p.Pro238Leu was identified. The observed variant … (more)
A Homozygote Missense variant c.713C>T in Exon 7 of the PPT1 gene that results in the amino acid substitution p.Pro238Leu was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic(Variant ID 236407). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
|
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Likely pathogenic
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204151.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Pathogenic
(Sep 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001585367.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with Batten disease (PMID: 30541466). This sequence change replaces proline, which is neutral and non-polar, with leucine, … (more)
This missense change has been observed in individual(s) with Batten disease (PMID: 30541466). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 238 of the PPT1 protein (p.Pro238Leu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 236407). For these reasons, this variant has been classified as Pathogenic. 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. (less)
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086768.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated palmitoyl protein thioesterase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has been observed as homozygous in multiple individuals with neuronal ceroid lipofuscinosis or related features (PMIDs: 30541466, 34849271, 31069529). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Individuals homozygous for this variant were shown to have minimal palmitoyl protein thioesterase activity (PMID: 30541466). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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|
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Likely pathogenic
(Nov 27, 2015)
|
no assertion criteria provided
Method: research
|
Neuronal ceroid lipofuscinosis 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000282513.1
First in ClinVar: Jun 25, 2016 Last updated: Jun 25, 2016 |
Comment:
Variant c.713C>T/p.P238L (ENST00000433473) found to be pathogenic by online software Mutation Taster, SIFT and Polyphen2
Observation 1:
Clinical Features:
Seizures (present) , Cerebral atrophy (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Indian
Geographic origin: India
Tissue: Blood
Method: Polymerase Chain Reaction followed by bi-directional Sanger sequencing was performed covering all exons and exon-intron boundaries of the PPT1 gene.
Observation 2:
Clinical Features:
Seizures (present) , Cerebral atrophy (present) , Reduced visual acuity (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Indian
Geographic origin: India
Tissue: Blood
Method: Polymerase Chain Reaction followed by bi-directional Sanger sequencing was performed covering all exons and exon-intron boundaries of the PPT1 gene.
|
Comment:
Comment:
This missense change has been observed in individual(s) with Batten disease (PMID: 30541466). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 238 of the PPT1 protein (p.Pro238Leu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 236407). For these reasons, this variant has been classified as Pathogenic. 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.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated palmitoyl protein thioesterase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has been observed as homozygous in multiple individuals with neuronal ceroid lipofuscinosis or related features (PMIDs: 30541466, 34849271, 31069529). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Individuals homozygous for this variant were shown to have minimal palmitoyl protein thioesterase activity (PMID: 30541466). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Variant c.713C>T/p.P238L (ENST00000433473) found to be pathogenic by online software Mutation Taster, SIFT and Polyphen2
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
effect on protein activity
|
|
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000282513.1
|
Comment:
Significantly reduced activity of PPT1 enzyme
|
Comment:
A Homozygote Missense variant c.713C>T in Exon 7 of the PPT1 gene that results in the amino acid substitution p.Pro238Leu was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic(Variant ID 236407). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
Comment:
This missense change has been observed in individual(s) with Batten disease (PMID: 30541466). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 238 of the PPT1 protein (p.Pro238Leu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 236407). For these reasons, this variant has been classified as Pathogenic. 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.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated palmitoyl protein thioesterase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has been observed as homozygous in multiple individuals with neuronal ceroid lipofuscinosis or related features (PMIDs: 30541466, 34849271, 31069529). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Individuals homozygous for this variant were shown to have minimal palmitoyl protein thioesterase activity (PMID: 30541466). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Variant c.713C>T/p.P238L (ENST00000433473) found to be pathogenic by online software Mutation Taster, SIFT and Polyphen2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Neuronal Ceroid Lipofuscinosis: Clinical and Laboratory Profile in Children from Tertiary Care Centre in South India. | Gowda VK | Journal of pediatric genetics | 2020 | PMID: 34849271 |
| Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients. | Ganapathy A | Journal of neurology | 2019 | PMID: 31069529 |
| Batten disease: biochemical and molecular characterization revealing novel PPT1 and TPP1 gene mutations in Indian patients. | Sheth J | BMC neurology | 2018 | PMID: 30541466 |
Text-mined citations for rs878853322 ...
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 Nov 10, 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.