NM_000310.4(PPT1):c.325T>G (p.Tyr109Asp) AND Neuronal ceroid lipofuscinosis 1

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 24, 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:: RCV000049601.8

Allele description [Variation Report for NM_000310.4(PPT1):c.325T>G (p.Tyr109Asp)]

NM_000310.4(PPT1):c.325T>G (p.Tyr109Asp)

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.325T>G (p.Tyr109Asp)

Other names:

p.Y109D:TAC>GAC

HGVS:

NC_000001.11:g.40092082A>C
NG_009192.1:g.10389T>G
NM_000310.4:c.325T>GMANE SELECT
NM_001142604.2:c.125-2570T>G
NM_001363695.2:c.325T>G
NP_000301.1:p.Tyr109Asp
NP_000301.1:p.Tyr109Asp
NP_001350624.1:p.Tyr109Asp
LRG_690t1:c.325T>G
LRG_690:g.10389T>G
LRG_690p1:p.Tyr109Asp
NC_000001.10:g.40557754A>C
NM_000310.3:c.325T>G
P50897:p.Tyr109Asp

Protein change:

Y109D

Links:

UniProtKB: P50897#VAR_005552; dbSNP: rs386833642

NCBI 1000 Genomes Browser:

rs386833642

Molecular consequence:

NM_001142604.2:c.125-2570T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000310.4:c.325T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363695.2:c.325T>G - 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
SCV000082008	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]
SCV001219531	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9664077, 10191107, 21990111, 11440996, 28492532
SCV002768749	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004204140	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2023)	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: SCV000082008

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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S.

Das AK, Becerra CH, Yi W, Lu JY, Siakotos AN, Wisniewski KE, Hofmann SL.

J Clin Invest. 1998 Jul 15;102(2):361-70.

PubMed [citation]

PMID:: 9664077
PMCID:: PMC508894

Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency.

Hofmann SL, Das AK, Yi W, Lu JY, Wisniewski KE.

Mol Genet Metab. 1999 Apr;66(4):234-9.

PubMed [citation]

PMID:: 10191107

See all PubMed Citations (6)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082008.1

#	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 Invitae, SCV001219531.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	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, SCV002768749.1

#	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_v1.1.1, 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)

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

From Baylor Genetics, SCV004204140.1

#	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: Feb 20, 2024

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