NM_000310.4(PPT1):c.541G>A (p.Val181Met) AND Neuronal ceroid lipofuscinosis 1

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jan 29, 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:: RCV000169209.18

Allele description [Variation Report for NM_000310.4(PPT1):c.541G>A (p.Val181Met)]

NM_000310.4(PPT1):c.541G>A (p.Val181Met)

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.541G>A (p.Val181Met)

HGVS:

NC_000001.11:g.40080483C>T
NG_009192.1:g.21988G>A
NM_000310.4:c.541G>AMANE SELECT
NM_001142604.2:c.232G>A
NM_001363695.2:c.541G>A
NP_000301.1:p.Val181Met
NP_000301.1:p.Val181Met
NP_001136076.1:p.Val78Met
NP_001350624.1:p.Val181Met
LRG_690t1:c.541G>A
LRG_690:g.21988G>A
LRG_690p1:p.Val181Met
NC_000001.10:g.40546155C>T
NM_000310.3:c.541G>A
P50897:p.Val181Met

Protein change:

V181M

Links:

UniProtKB: P50897#VAR_005557; dbSNP: rs148412181

NCBI 1000 Genomes Browser:

rs148412181

Molecular consequence:

NM_000310.4:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001142604.2:c.232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363695.2:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000220464	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jun 27, 2014)	unknown	literature only	PubMed (6) [See all records that cite these PMIDs] 11073228, 12796825, 9664077, 10649502, 11440996, 23374165 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000958226	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10191107, 10649502, 15464427, 22387303, 23374165, 30541466, 9664077, 11440996, 28878621, 19302939, 21499717, 28492532
SCV000965817	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 4, 2016)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001361117	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 11, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9664077, 23374165, 22387303 Citation Link,
SCV001571358	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 12, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002085986	Natera, Inc.	no assertion criteria provided	Pathogenic (Jun 7, 2021)	germline	clinical testing
SCV003826627	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004204132	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 10, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Neuronal ceroid lipofuscinoses: research update.

Wisniewski KE, Kida E, Connell F, Zhong N.

Neurol Sci. 2000;21(3 Suppl):S49-56. Review.

PubMed [citation]

PMID:: 11073228

Clinicopathological and molecular characterization of neuronal ceroid lipofuscinosis in the Portuguese population.

Teixeira C, Guimarães A, Bessa C, Ferreira MJ, Lopes L, Pinto E, Pinto R, Boustany RM, Sá Miranda MC, Ribeiro MG.

J Neurol. 2003 Jun;250(6):661-7.

PubMed [citation]

PMID:: 12796825

See all PubMed Citations (15)

Details of each submission

From Counsyl, SCV000220464.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (6)

#	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 Invitae, SCV000958226.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 181 of the PPT1 protein (p.Val181Met). This variant is present in population databases (rs148412181, gnomAD 0.02%). This missense change has been observed in individuals with neuronal ceroid lipofucinosis (NCL) (PMID: 9664077, 10191107, 10649502, 15464427, 19302939, 22387303, 23374165, 30541466). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188857). 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: 9664077, 11440996, 28878621). This variant disrupts the p.Val181 amino acid residue in PPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19302939, 21499717). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV000965817.1

#	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	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361117.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: PPT1 c.541G>A (p.Val181Met) results in a 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 8.7e-05 in 277014 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PPT1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (8.7e-05 vs 0.00073), allowing no conclusion about variant significance. c.541G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, Das_1998, Santorelli_2013, Poyato_2012). 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 enzyme activity. The most pronounced variant effect results in <10% of normal activity (Das_1998, Poyato_2012). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was 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 Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SCV001571358.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	no	clinical testing	PubMed (1)

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

From Natera, Inc., SCV002085986.1

#	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 Revvity Omics, Revvity, SCV003826627.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004204132.1

#	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: Mar 30, 2024

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