Variant summary: PPT1 c.541G>T (p.Val181Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251372 control chromosomes. c.541G>T has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Simonati_2009, Perez-Poyato_2011, Pezzini_2017, Jiliani_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal PPT1 enzyme activity (example, Perez-Poyato_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. 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.541G>T (p.Val181Leu)
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.
(8)
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
8
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.541G>T (p.Val181Leu)
Variation ID: 56202 Accession: VCV000056202.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.2 1: 40080483 (GRCh38) [ NCBI UCSC ] 1: 40546155 (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 Nov 24, 2024 Mar 18, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000310.4:c.541G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000301.1:p.Val181Leu missense NM_001142604.2:c.232G>T NP_001136076.1:p.Val78Leu missense NM_001363695.2:c.541G>T NP_001350624.1:p.Val181Leu missense NC_000001.11:g.40080483C>A NC_000001.10:g.40546155C>A NG_009192.1:g.21988G>T LRG_690:g.21988G>T LRG_690t1:c.541G>T LRG_690p1:p.Val181Leu P50897:p.Val181Leu - Protein change
- V181L, V78L
- Other names
- -
- Canonical SPDI
- NC_000001.11:40080482:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 | - | - |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 18, 2024 | RCV000049613.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 6, 2023 | RCV000436288.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 31, 2021 | RCV001526944.1 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 12, 2022 | RCV004584340.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 31, 2021)
|
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: SCV001737713.1
First in ClinVar: Jun 23, 2021 Last updated: Jun 23, 2021 |
Comment:
Variant summary: PPT1 c.541G>T (p.Val181Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: PPT1 c.541G>T (p.Val181Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251372 control chromosomes. c.541G>T has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Simonati_2009, Perez-Poyato_2011, Pezzini_2017, Jiliani_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal PPT1 enzyme activity (example, Perez-Poyato_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Dec 09, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000485419.2
First in ClinVar: Jul 24, 2013 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000520956.5
First in ClinVar: Mar 08, 2017 Last updated: Mar 26, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12125808, 21499717, 19302939, 21990111, 15965709, 28878621, 34426522, 31741823, 34440436, 10477428, 22387303, 12796825) (less)
|
|
|
Pathogenic
(Dec 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001211250.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 181 of the PPT1 protein (p.Val181Leu). … (more)
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 181 of the PPT1 protein (p.Val181Leu). This variant is present in population databases (rs148412181, gnomAD 0.007%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (NCL) (PMID: 10477428, 19302939, 21499717). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56202). 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%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 28878621). This variant disrupts the p.Val181 amino acid residue in PPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9664077, 11440996, 22387303, 23374165, 28878621). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204145.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Apr 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002499694.2
First in ClinVar: Apr 23, 2022 Last updated: Jul 07, 2024 |
Comment:
ACMG categories: PS3,PS4,PM2,PP3,PP5
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Autistic behavior (present) , Absent speech (present) , Motor stereotypies (present) , Increased overbite (present)
Age: 0-9 years
Sex: female
Tissue: blood
|
|
|
Pathogenic
(Nov 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413541.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP3, PP4, PM2_moderate, PM3_strong, PM5, PS4_moderate
Number of individuals with the variant: 1
|
|
|
probable-pathogenic
(-)
|
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: SCV000082020.1
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:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12125808, 21499717, 19302939, 21990111, 15965709, 28878621, 34426522, 31741823, 34440436, 10477428, 22387303, 12796825)
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 181 of the PPT1 protein (p.Val181Leu). This variant is present in population databases (rs148412181, gnomAD 0.007%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (NCL) (PMID: 10477428, 19302939, 21499717). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56202). 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%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 28878621). This variant disrupts the p.Val181 amino acid residue in PPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9664077, 11440996, 22387303, 23374165, 28878621). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
ACMG categories: PS3,PS4,PM2,PP3,PP5
Comment:
PP3, PP4, PM2_moderate, PM3_strong, PM5, PS4_moderate
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.541G>T (p.Val181Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251372 control chromosomes. c.541G>T has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Simonati_2009, Perez-Poyato_2011, Pezzini_2017, Jiliani_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal PPT1 enzyme activity (example, Perez-Poyato_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12125808, 21499717, 19302939, 21990111, 15965709, 28878621, 34426522, 31741823, 34440436, 10477428, 22387303, 12796825)
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 181 of the PPT1 protein (p.Val181Leu). This variant is present in population databases (rs148412181, gnomAD 0.007%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (NCL) (PMID: 10477428, 19302939, 21499717). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56202). 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%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 28878621). This variant disrupts the p.Val181 amino acid residue in PPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9664077, 11440996, 22387303, 23374165, 28878621). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
ACMG categories: PS3,PS4,PM2,PP3,PP5
Comment:
PP3, PP4, PM2_moderate, PM3_strong, PM5, PS4_moderate
Comment:
Converted during submission to Likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center. | Barbosa-Gouveia S | Genes | 2021 | PMID: 34440436 |
| High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses. | Jilani A | JIMD reports | 2019 | PMID: 31741823 |
| Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin. | Mathavarajah S | Cells | 2018 | PMID: 30380624 |
| The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells. | Pezzini F | Frontiers in molecular neuroscience | 2017 | PMID: 28878621 |
| Molecular epidemiology of childhood neuronal ceroid-lipofuscinosis in Italy. | Santorelli FM | Orphanet journal of rare diseases | 2013 | PMID: 23374165 |
| Infantile neuronal ceroid lipofuscinosis: follow-up on a Spanish series. | Pérez Poyato MS | Gene | 2012 | PMID: 22387303 |
| 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 |
| Juvenile neuronal ceroid lipofuscinosis: clinical course and genetic studies in Spanish patients. | Pérez-Poyato MS | Journal of inherited metabolic disease | 2011 | PMID: 21499717 |
| Variant late infantile neuronal ceroid lipofuscinosis because of CLN1 mutations. | Simonati A | Pediatric neurology | 2009 | PMID: 19302939 |
| Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. | Mole SE | Neurogenetics | 2005 | PMID: 15965709 |
| Biochemical analysis of mutations in palmitoyl-protein thioesterase causing infantile and late-onset forms of neuronal ceroid lipofuscinosis. | Das AK | Human molecular genetics | 2001 | PMID: 11440996 |
| Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. | Mole SE | Human mutation | 1999 | PMID: 10477428 |
| Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. | Das AK | The Journal of clinical investigation | 1998 | PMID: 9664077 |
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Text-mined citations for rs148412181 ...
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 25, 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.