NM_000310.4(PPT1):c.287G>A (p.Cys96Tyr) AND Neuronal ceroid lipofuscinosis 1

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jun 16, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000049599.10

Allele description [Variation Report for NM_000310.4(PPT1):c.287G>A (p.Cys96Tyr)]

NM_000310.4(PPT1):c.287G>A (p.Cys96Tyr)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.2

Genomic location:

Preferred name:

NM_000310.4(PPT1):c.287G>A (p.Cys96Tyr)

HGVS:

NC_000001.11:g.40092120C>T
NG_009192.1:g.10351G>A
NM_000310.4:c.287G>AMANE SELECT
NM_001142604.2:c.125-2608G>A
NM_001363695.2:c.287G>A
NP_000301.1:p.Cys96Tyr
NP_000301.1:p.Cys96Tyr
NP_001350624.1:p.Cys96Tyr
LRG_690t1:c.287G>A
LRG_690:g.10351G>A
LRG_690p1:p.Cys96Tyr
NC_000001.10:g.40557792C>T
NM_000310.3:c.287G>A

Protein change:

C96Y

Links:

NCBI 1000 Genomes Browser:

rs386833640

Molecular consequence:

NM_001142604.2:c.125-2608G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000310.4:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363695.2:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000082006	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]
SCV000800627	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Nov 26, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11589012, 23772246 Citation Link,
SCV001258865	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Aug 16, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12125808, 15965709, 11589012, 21990111 Citation Link,
SCV002279001	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23772246, 28492532

Description

FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000082006

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	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2).

Hofmann SL, Atashband A, Cho SK, Das AK, Gupta P, Lu JY.

Curr Mol Med. 2002 Aug;2(5):423-37. Review.

PubMed [citation]

PMID:: 12125808

Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses.

Mole SE, Williams RE, Goebel HH.

Neurogenetics. 2005 Sep;6(3):107-26. Epub 2005 Sep 28. Review.

PubMed [citation]

PMID:: 15965709

See all PubMed Citations (6)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082006.1

#	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, SCV000800627.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Illumina Laboratory Services, Illumina, SCV001258865.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002279001.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 56188). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 23772246). This variant is present in population databases (rs386833640, gnomAD 0.004%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 96 of the PPT1 protein (p.Cys96Tyr).

#	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

Last Updated: Sep 29, 2024

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