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

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Apr 12, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000169209.7

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

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

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
HGVS:
  • NC_000001.11:g.40080483C>T
  • NG_009192.1:g.21988G>A
  • NM_000310.3:c.541G>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_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
  • P50897:p.Val181Met
Protein change:
V181M
Links:
UniProtKB: P50897#VAR_005557; dbSNP: rs148412181
NCBI 1000 Genomes Browser:
rs148412181
Molecular consequence:
  • NM_000310.3: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:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000220464Counsylcriteria provided, single submitter
Likely pathogenic
(Jun 27, 2014)
unknownliterature only

PubMed (6)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000958226Invitaecriteria provided, single submitter
Pathogenic
(Oct 14, 2020)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000965817Equipe Genetique des Anomalies du Developpement, Université de Bourgognecriteria provided, single submitter
Pathogenic
(Jan 4, 2016)
inheritedclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001361117Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Mar 11, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001571358Centre for Inherited Metabolic Diseases, Karolinska University Hospitalcriteria provided, single submitter
Pathogenic
(Apr 12, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedinheritedyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedliterature 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, SCV000220464.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000958226.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This sequence change replaces valine with methionine at codon 181 of the PPT1 protein (p.Val181Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs148412181, ExAC 0.03%). This variant has been observed in several individuals affected with neuronal ceroid lipofucinosis (NCL) (PMID: 9664077, 10649502, 15464427, 19302939, 30541466, 10191107) and has been observed to segregate with NCL in several families (PMID: 22387303, 23374165). ClinVar contains an entry for this variant (Variation ID: 188857). Experimental studies have shown that this missense change results in loss of PPT enzyme activity in a neuroblastoma cell line (PMID: 28878621) as well as in patient lymphoblasts (PMID: 9664077, 11440996). Variants that disrupt the p.Val181 amino acid residue in PPT1 have been observed in affected individuals (PMID: 21499717, 19302939). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV000965817.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SCV001571358.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednoclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not provideddiscovery1not providednot providednot provided

Last Updated: Jun 14, 2021

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