ClinVar Genomic variation as it relates to human health
NM_000310.4(PPT1):c.223A>C (p.Thr75Pro)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000310.4(PPT1):c.223A>C (p.Thr75Pro)
Variation ID: 8900 Accession: VCV000008900.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40092409 (GRCh38) [ NCBI UCSC ] 1: 40558081 (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 Apr 4, 2013 May 1, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000310.4:c.223A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000301.1:p.Thr75Pro missense NM_001142604.2:c.125-2897A>C intron variant NM_001363695.2:c.223A>C NP_001350624.1:p.Thr75Pro missense NC_000001.11:g.40092409T>G NC_000001.10:g.40558081T>G NG_009192.1:g.10062A>C LRG_690:g.10062A>C LRG_690t1:c.223A>C LRG_690p1:p.Thr75Pro P50897:p.Thr75Pro - Protein change
- T75P
- Other names
- p.T75P:ACC>CCC
- Canonical SPDI
- NC_000001.11:40092408:T: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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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 |
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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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000009451.19 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 8, 2021 | RCV000188709.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2021 | RCV001723555.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 9, 2022 | RCV002426497.2 | |
PPT1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jan 23, 2023 | RCV003407309.4 |
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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Pathogenic
(Nov 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Ceroid lipofuscinosis neuronal 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918089.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PPT1 c.223A>C (p.Thr75Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: PPT1 c.223A>C (p.Thr75Pro) results in a non-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 1.6e-05 in 246324 control chromosomes (gnomAD).The variant, c.223A>C, has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease), including at least one homozygote (Mitchison_1998). 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 activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 09, 2019)
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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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Myriad Genetics, Inc.
Accession: SCV001193860.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000310.3(PPT1):c.223A>C(T75P) is classified as pathogenic in the context of PPT1-related neuronal ceroid lipofuscinosis and is associated with the juvenile form of this disease. Sources cited … (more)
NM_000310.3(PPT1):c.223A>C(T75P) is classified as pathogenic in the context of PPT1-related neuronal ceroid lipofuscinosis and is associated with the juvenile form of this disease. Sources cited for classification include the following: PMID 9425237, 9664077 and 23539563. Classification of NM_000310.3(PPT1):c.223A>C(T75P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Feb 07, 2021)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002064480.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the PPT1 gene demonstrated a sequence change, c.223A>C, in exon 2 that results in an amino acid change, p.Thr75Pro. This sequence … (more)
DNA sequence analysis of the PPT1 gene demonstrated a sequence change, c.223A>C, in exon 2 that results in an amino acid change, p.Thr75Pro. This sequence change has been described in the gnomAD database with a low frequency of 0.006% in African/African American subpopulation (dbSNP rs137852696). This sequence change has previously been described in the homozygous and compound heterozygous states in individuals and families with PPT1-related disorders (PMIDs: 9425237, 26510000). The p.Thr75Pro change affects a poorly conserved amino acid residue of the PPT1 protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr75Pro substitution. Functional studies suggest p.Thr75Pro reduces PPT1 enzyme activity (PMID: 23539563). Collectively these evidences suggest this p.Thr75Pro variant is pathogenic. (less)
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Pathogenic
(Oct 08, 2021)
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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: SCV000242333.13
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate the variant results in reduced PPT1 enzyme activity (Miller et al., 2013); Not observed at significant frequency in large population cohorts … (more)
Published functional studies demonstrate the variant results in reduced PPT1 enzyme activity (Miller et al., 2013); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14997939, 10649502, 26510000, 11520175, 19793631, 16720047, 22778232, 23542453, 11073228, 10781062, 16759889, 9664077, 20346914, 23857568, 29655203, 28559085, 23539563, 9425237) (less)
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Pathogenic
(Jan 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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PPT1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004113190.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PPT1 c.223A>C variant is predicted to result in the amino acid substitution p.Thr75Pro. This variant has been documented in the homozygous and compound heterozygous … (more)
The PPT1 c.223A>C variant is predicted to result in the amino acid substitution p.Thr75Pro. This variant has been documented in the homozygous and compound heterozygous states as causative for neuronal ceroid lipofuscinosis 1 (CLN1) in several affected patients (Mitchison et al.1998. PubMed ID: 9425237; Das et al. 1998. PubMed ID: 9664077). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-40558081-T-G). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 09, 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:
germline
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Revvity Omics, Revvity
Accession: SCV002019505.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Apr 01, 2021)
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criteria provided, single submitter
Method: curation
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Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950329.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Thr75Pro variant in PPT1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The p.Thr75Pro variant in PPT1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S, PS3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
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Pathogenic
(May 17, 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: SCV002778159.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 20, 2023)
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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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Baylor Genetics
Accession: SCV004204137.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 22, 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: SCV001397118.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 75 of the PPT1 protein (p.Thr75Pro). … (more)
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 75 of the PPT1 protein (p.Thr75Pro). This variant is present in population databases (rs137852696, gnomAD 0.007%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis 1 (PMID: 9425237, 26510000, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8900). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PPT1 function (PMID: 23539563). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 09, 2022)
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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: SCV002726863.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.223A>C (p.T75P) alteration is located in exon 2 (coding exon 2) of the PPT1 gene. This alteration results from a A to C substitution … (more)
The c.223A>C (p.T75P) alteration is located in exon 2 (coding exon 2) of the PPT1 gene. This alteration results from a A to C substitution at nucleotide position 223, causing the threonine (T) at amino acid position 75 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (4/251446) total alleles studied. The highest observed frequency was 0.01% (1/16256) of African alleles. This mutation has been identified in multiple individuals in the compound heterozygous and homozygous state (Miller, 2013; Mitchison, 1998; Metelitsina, 2016; Das, 1998; Stone, 2017; Jilani, 2019). This amino acid position is not well conserved in available vertebrate species. This alteration has been shown to reduce PPT1 enzyme activity (Miller, 2013). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jul 15, 1998)
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no assertion criteria provided
Method: literature only
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CEROID LIPOFUSCINOSIS, NEURONAL, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029669.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Mitchison et al. (1998) found that a thr75-to-pro (T75P) missense mutation in the PPT1 gene accounted for 9 of 22 disease chromosomes in 11 patients … (more)
Mitchison et al. (1998) found that a thr75-to-pro (T75P) missense mutation in the PPT1 gene accounted for 9 of 22 disease chromosomes in 11 patients with juvenile-onset CLN1 (256730). In 1 of the 11 patients the T75P was homozygous; in 7 others it was present in compound heterozygous state with a nonsense mutation, either arg151-to-ter (R151X; 600722.0006) or leu10-to-ter (L10X; 600722.0005). In 29 U.S. and Canadian families with PPT1 deficiency, Das et al. (1998) found that the T75P mutation accounted for 13% of the alleles and was associated with a late onset and protracted clinical course. (less)
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Pathogenic
(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: SCV001464024.1
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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The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses. | Jilani A | JIMD reports | 2019 | PMID: 31741823 |
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
BATTEN DISEASE CAUSED BY A NOVEL MUTATION IN THE PPT1 GENE. | Metelitsina TI | Retinal cases & brief reports | 2016 | PMID: 26510000 |
The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis. | Miller JN | Human molecular genetics | 2013 | PMID: 23539563 |
Neuronal trafficking of palmitoyl protein thioesterase provides an excellent model to study the effects of different mutations which cause infantile neuronal ceroid lipofuscinocis. | Salonen T | Molecular and cellular neurosciences | 2001 | PMID: 11520175 |
Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. | Das AK | The Journal of clinical investigation | 1998 | PMID: 9664077 |
Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. | Mitchison HM | Human molecular genetics | 1998 | PMID: 9425237 |
Text-mined citations for rs137852696 ...
HelpRecord last updated May 19, 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.