Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to aspartic acid (exon 3). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 Heterozygote, 0 Homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (palmitoyl protein thioesterase domain, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Das, AK. et al. (1998), Hofmann, SL. et al. (1999), Das, AK. et al. (2001), Kousi, M. et al. (2012), Teixeira, C. et al. (2013)). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence supporting abnormal protein function (Das, AK. et al. (2001)). (P) 1208 - Inheritance information for this variant is not currently available. (N)
ClinVar Genomic variation as it relates to human health
NM_000310.4(PPT1):c.325T>G (p.Tyr109Asp)
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.
(5)
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
5
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.325T>G (p.Tyr109Asp)
Variation ID: 56190 Accession: VCV000056190.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.2 1: 40092082 (GRCh38) [ NCBI UCSC ] 1: 40557754 (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 Jun 17, 2024 Jan 24, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000310.4:c.325T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000301.1:p.Tyr109Asp missense NM_001142604.2:c.125-2570T>G intron variant NM_001363695.2:c.325T>G NP_001350624.1:p.Tyr109Asp missense NC_000001.11:g.40092082A>C NC_000001.10:g.40557754A>C NG_009192.1:g.10389T>G LRG_690:g.10389T>G LRG_690t1:c.325T>G LRG_690p1:p.Tyr109Asp P50897:p.Tyr109Asp - Protein change
- Y109D
- Other names
-
p.Y109D:TAC>GAC
- Canonical SPDI
- NC_000001.11:40092081:A:C
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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 |
694 | 722 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV000049601.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 11, 2022 | RCV000188711.3 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 25, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768749.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to aspartic acid (exon 3). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 Heterozygote, 0 Homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (palmitoyl protein thioesterase domain, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Das, AK. et al. (1998), Hofmann, SL. et al. (1999), Das, AK. et al. (2001), Kousi, M. et al. (2012), Teixeira, C. et al. (2013)). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence supporting abnormal protein function (Das, AK. et al. (2001)). (P) 1208 - Inheritance information for this variant is not currently available. (N) (less)
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001219531.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 109 of the PPT1 protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 109 of the PPT1 protein (p.Tyr109Asp). This variant is present in population databases (rs386833642, gnomAD 0.0009%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 10191107, 21990111). ClinVar contains an entry for this variant (Variation ID: 56190). 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%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000242335.13
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with significantly impaired enzyme activity (Das et al., 2001); Not observed at significant frequency in large population cohorts … (more)
Published functional studies demonstrate a damaging effect with significantly impaired enzyme activity (Das et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17565660, 10191107, 21990111, 11440996, 9664077, 11073228, 15719035) (less)
|
|
|
Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204140.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
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: SCV000082008.1
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:
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 109 of the PPT1 protein (p.Tyr109Asp). This variant is present in population databases (rs386833642, gnomAD 0.0009%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 10191107, 21990111). ClinVar contains an entry for this variant (Variation ID: 56190). 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%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996). For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate a damaging effect with significantly impaired enzyme activity (Das et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17565660, 10191107, 21990111, 11440996, 9664077, 11073228, 15719035)
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:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to aspartic acid (exon 3). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 Heterozygote, 0 Homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (palmitoyl protein thioesterase domain, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Das, AK. et al. (1998), Hofmann, SL. et al. (1999), Das, AK. et al. (2001), Kousi, M. et al. (2012), Teixeira, C. et al. (2013)). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence supporting abnormal protein function (Das, AK. et al. (2001)). (P) 1208 - Inheritance information for this variant is not currently available. (N)
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 109 of the PPT1 protein (p.Tyr109Asp). This variant is present in population databases (rs386833642, gnomAD 0.0009%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 10191107, 21990111). ClinVar contains an entry for this variant (Variation ID: 56190). 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%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996). For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate a damaging effect with significantly impaired enzyme activity (Das et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17565660, 10191107, 21990111, 11440996, 9664077, 11073228, 15719035)
Comment:
Converted during submission to Likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| 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 |
| Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency. | Hofmann SL | Molecular genetics and metabolism | 1999 | PMID: 10191107 |
| Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. | Das AK | The Journal of clinical investigation | 1998 | PMID: 9664077 |
Text-mined citations for rs386833642 ...
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 Sep 29, 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.