ClinVar Genomic variation as it relates to human health
NM_000310.4(PPT1):c.364A>T (p.Arg122Trp)
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.364A>T (p.Arg122Trp)
Variation ID: 8899 Accession: VCV000008899.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40091398 (GRCh38) [ NCBI UCSC ] 1: 40557070 (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 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000310.4:c.364A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000301.1:p.Arg122Trp missense NM_001142604.2:c.125-1886A>T intron variant NM_001363695.2:c.364A>T NP_001350624.1:p.Arg122Trp missense NC_000001.11:g.40091398T>A NC_000001.10:g.40557070T>A NG_009192.1:g.11073A>T LRG_690:g.11073A>T LRG_690t1:c.364A>T LRG_690p1:p.Arg122Trp P50897:p.Arg122Trp - Protein change
- R122W
- Other names
- p.R122W:AGG>TGG
- Canonical SPDI
- NC_000001.11:40091397:T: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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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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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
The Genome Aggregation Database (gnomAD) 0.00061
Exome Aggregation Consortium (ExAC) 0.00068
The Genome Aggregation Database (gnomAD), exomes 0.00070
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 | ||
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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
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 |
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
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. |
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Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2024 | RCV000009450.23 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 7, 2022 | RCV000188724.10 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 6, 2011 | RCV000581618.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2016 | RCV000623227.3 |
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. |
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Pathogenic
(May 06, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363469.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PPT1 c.364A>T (p.Arg122Trp) 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.364A>T (p.Arg122Trp) 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 0.0007 in 250432 control chromosomes (gnomAD). c.364A>T has been reported in the literature in numerous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and is considered a Finnish founder mutation. The variant has been functionally shown to impact enzyme activity (Vesa_1995). 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. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 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:
germline
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Revvity Omics, Revvity
Accession: SCV003826604.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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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: SCV001194212.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000310.3(PPT1):c.364A>T(R122W) is classified as pathogenic in the context of PPT1-related neuronal ceroid lipofuscinosis and is associated with the infantile form of this disease. Sources cited … (more)
NM_000310.3(PPT1):c.364A>T(R122W) is classified as pathogenic in the context of PPT1-related neuronal ceroid lipofuscinosis and is associated with the infantile form of this disease. Sources cited for classification include the following: PMID 7637805. Classification of NM_000310.3(PPT1):c.364A>T(R122W) 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
(Apr 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001571359.1
First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021 |
Family history: no
Secondary finding: no
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Pathogenic
(Dec 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001712988.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4, PM3, PP4, PP5
Number of individuals with the variant: 1
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Pathogenic
(Sep 23, 2021)
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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: SCV002780411.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 07, 2022)
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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: SCV000242348.13
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect resulting in impairment of enzyme activity (Lyly et al., 2007; Vesa et al., 1995); In silico analysis supports … (more)
Published functional studies demonstrate a damaging effect resulting in impairment of enzyme activity (Lyly et al., 2007; Vesa et al., 1995); 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: 20561933, 22778232, 14997939, 11754099, 26026925, 16759889, 24997880, 16542649, 12069847, 19793631, 26795593, 9664077, 17388982, 10781062, 20346914, 16644870, 19941651, 16930952, 11073228, 25091425, 25865307, 7637805, 25525159, 21228398, 21990111, 28559085, 31980526, 17565660, 33726816) (less)
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Pathogenic
(Oct 16, 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: SCV004204129.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 13, 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: SCV000762929.7
First in ClinVar: Oct 01, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 122 of the PPT1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 122 of the PPT1 protein (p.Arg122Trp). This variant is present in population databases (rs137852695, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with infantile neuronal ceroid lipofuscinosis (INCL) (PMID: 7637805, 9664077, 26795593). It is commonly reported in individuals of Finnish ancestry (PMID: 7637805, 9664077, 19941651, 21990111, 26795593; INCL). ClinVar contains an entry for this variant (Variation ID: 8899). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPT1 function (PMID: 7637805, 10781062). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 02, 2016)
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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: SCV000740797.4
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The p.R122W pathogenic mutation (also known as c.364A>T), located in coding exon 4 of the PPT1 gene, results from an A to T substitution at … (more)
The p.R122W pathogenic mutation (also known as c.364A>T), located in coding exon 4 of the PPT1 gene, results from an A to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by tryptophan, an amino acid with dissimilar properties. This pathogenic mutation has been identified in the homozygous state or with another alteration in PPT1 in multiple individuals with infantile neuronal ceroid lipofuscinoses (NCL) and is a founder mutation in the Finnish population (Vesa J et al. Nature. 1995; 376(6541):584-7; Das AK et al. J Clin Invest. 1998; 102(2):361-70; Kousi M et al. Hum Mutat. 2012; 33(1):42-63). Functional studies in patient cells and in vitro studies have found this mutation to result in undetectable enzyme activity and accumulation of the polypeptide in the endoplasmic reticulum (Vesa J et al. Nature. 1995; 376(6541):584-7; Das AK et al. Hum Mol Genet. 2001;10(13):1431-9; Lyly A et al. BMC Cell Biol. 2007; 8:22). In addition, based on structural analysis, this mutation is anticipated to result in a significant decrease in structural stability (Bellizzi JJ et al. Proc Natl Acad Sci USA. 2000; 97(9):4573-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Aug 17, 1995)
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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: SCV000029668.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In patients with classic infantile-onset CLN1 (256730) from 40 of 42 Finnish families, Vesa et al. (1995) identified a homozygous 364A-T transversion in the PPT1 … (more)
In patients with classic infantile-onset CLN1 (256730) from 40 of 42 Finnish families, Vesa et al. (1995) identified a homozygous 364A-T transversion in the PPT1 gene, resulting in an arg122-to-trp (R122W) substitution. Unaffected parents were heterozygous for the mutation. The arg122 residue is immediately adjacent to a lipase consensus sequence that contains the putative active-site serine of the protein. A heterozygous R122W substitution was identified in 3 of 200 control Finnish individuals, yielding a carrier frequency of 1 in 70. The findings were consistent with 1 major disease-causing mutation in the Finnish population resulting from a founder effect. In the remaining 2 Finnish families, patients were compound heterozygous for R122W and an uncharacterized null allele. Two of 17 non-Finnish patients, 1 German and 1 Estonian, were also homozygous for R122W. In vitro functional expression studies showed that the R122W mutant protein was retained in the endoplasmic reticulum, was not secreted, and had undetectable enzyme activity. (less)
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Pathogenic
(Jul 06, 2011)
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no assertion criteria provided
Method: clinical testing
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Neuronal ceroid lipofuscinosis
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692330.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Ceroid lipofuscinosis neuronal 1
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142297.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000310.3:c.364A>T in the PPT1 gene has an allele frequency of 0.006 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that c.364A>T has impaired … (more)
NM_000310.3:c.364A>T in the PPT1 gene has an allele frequency of 0.006 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that c.364A>T has impaired enzyme activity(PMID: 7637805). Helbig et al. reported a child with progressive Myoclonus Epilepsy barboring the compound heterozygous of c.364A>T (p.R122W) and c.353G>A (p.G118D) (PMID: 26795593); In addition, Vesa et al. reported that 40 of the 42 Finnish families, whose child were homozygous suffering Ceroid lipofuscinosis neuronal, and parents were heterozygous, suggesting a founder effect in Finnish population (PMID: 7637805); Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS4; PS3; PM3; PP4 (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: SCV001464020.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Neuronal ceroid lipofuscinosis 1
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000086760.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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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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Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. | Helbig KL | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26795593 |
Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2013 | PMID: 20301601 |
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 |
Novel interactions of CLN5 support molecular networking between Neuronal Ceroid Lipofuscinosis proteins. | Lyly A | BMC cell biology | 2009 | PMID: 19941651 |
Glycosylation, transport, and complex formation of palmitoyl protein thioesterase 1 (PPT1)--distinct characteristics in neurons. | Lyly A | BMC cell biology | 2007 | PMID: 17565660 |
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 |
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 |
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 |
Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. | Vesa J | Nature | 1995 | PMID: 7637805 |
Text-mined citations for rs137852695 ...
HelpRecord last updated May 01, 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.