NM_000310.4(PPT1):c.169dup (p.Met57fs) AND Neuronal ceroid lipofuscinosis 1

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Mar 21, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000049593.21

Allele description [Variation Report for NM_000310.4(PPT1):c.169dup (p.Met57fs)]

NM_000310.4(PPT1):c.169dup (p.Met57fs)

Gene:

PPT1:palmitoyl-protein thioesterase 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

1p34.2

Genomic location:

Preferred name:

NM_000310.4(PPT1):c.169dup (p.Met57fs)

HGVS:

NC_000001.11:g.40092469dup
NG_009192.1:g.10008dup
NM_000310.4:c.169dupMANE SELECT
NM_001142604.2:c.125-2951dup
NM_001363695.2:c.169dup
NP_000301.1:p.Met57fs
NP_000301.1:p.Met57fs
NP_001350624.1:p.Met57fs
LRG_690t1:c.169dup
LRG_690:g.10008dup
LRG_690p1:p.Met57fs
NC_000001.10:g.40558134_40558135insT
NC_000001.10:g.40558141dup
NM_000310.3:c.169dup
NM_000310.3:c.169dupA

Protein change:

M57fs

Links:

OMIM: 600722.0007; dbSNP: rs386833634

NCBI 1000 Genomes Browser:

rs386833634

Molecular consequence:

NM_000310.4:c.169dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363695.2:c.169dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001142604.2:c.125-2951dup - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Neuronal ceroid lipofuscinosis 1 (CLN1)
Synonyms:: CEROID LIPOFUSCINOSIS, NEURONAL, 1, VARIABLE AGE AT ONSET; CLN1 variable age at onset; Infantile CLN (type of CLN1); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009744; MedGen: C1850451; OMIM: 256730

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TMEFF1 is a neuron-specific restriction factor for herpes simplex virus
TMEFF1 is a neuron-specific restriction factor for herpes simplex virus
TMEFF1 is a neuron-specific restriction factor for herpes simplex virus

BioProject
Ndufa6 [Mastomys coucha]
Ndufa6 [Mastomys coucha]
Gene ID:116076712

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000029674	OMIM	no assertion criteria provided	Pathogenic (Apr 17, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000082000	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	not provided	not provided	PubMed (1) [See all records that cite this PMID]
SCV000220573	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 3, 2014)	unknown	literature only	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000284561	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9571187, 10679943, 21990111, 28492532
SCV001453964	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV003921784	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004204147	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 21, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Description

FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000082000

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

A novel insertion mutation (A169i) in the CLN1 gene is associated with infantile neuronal ceroid lipofuscinosis in an Italian patient.

Santorelli FM, Bertini E, Petruzzella V, Di Capua M, Calvieri S, Gasparini P, Zeviani M.

Biochem Biophys Res Commun. 1998 Apr 17;245(2):519-22.

PubMed [citation]

PMID:: 9571187

Detection of eight novel palmitoyl protein thioesterase (PPT) mutations underlying infantile neuronal ceroid lipofuscinosis (INCL;CLN1).

Salonen T, Järvelä I, Peltonen L, Jalanko A.

Hum Mutat. 2000;15(3):273-9.

PubMed [citation]

PMID:: 10679943

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000029674.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 4-year-old boy with infantile-onset CLN1 (256730), Santorelli et al. (1998) identified a single adenine insertion at nucleotide position 169 (160insA) in the PPT gene. The mutation was homozygous in the proband, heterozygous in his healthy parents, and not found in control alleles. The mutation led to an early stop codon, resulting in an abnormal and truncated PPT protein. The 4-year-old boy developed normally until the age of 12 months. He could sit and crawl; however, he never achieved independent walking. Psychomotor regression occurred over the subsequent 2 months. At age 14 months, he had lost most of his motor abilities and showed a progressive worsening of his clinical status. At approximately 18 months of age, he was hypotonic and also presented severe speech impairment, visual loss, and myoclonic seizures. Electroretinogram and visual evoked potentials were altered. MRI showed severe cerebral cortical atrophy with relative sparing of the cerebellum. Ultrastructural studies showed recurrent granular osmiophilic deposits in both endothelial cells and fibroblasts on skin biopsy.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082000.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000220573.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000284561.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Met57Asnfs*45) in the PPT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs386833634, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with infantile neuronal ceroid lipofuscinosis (PMID: 9571187, 10679943, 21990111). This variant is also known as 169 (A169i) and as c.162-163insA. ClinVar contains an entry for this variant (Variation ID: 56182). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001453964.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV003921784.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (SP) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and have been observed in individuals with neuronal ceroid lipofuscinosis (ClinVar, Decipher). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic in individuals with neuronal ceroid lipofuscinosis (ClinVar). (SP) 1201 - Heterozygous variant detected likely in trans with a second pathogenic heterozygous variant (p.(Arg151*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004204147.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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