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NM_000310.4(PPT1):c.413C>T (p.Ser138Leu) AND Neuronal ceroid lipofuscinosis 1

Germline classification:
Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:
Feb 24, 2024
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:
RCV000049605.12

Allele description [Variation Report for NM_000310.4(PPT1):c.413C>T (p.Ser138Leu)]

NM_000310.4(PPT1):c.413C>T (p.Ser138Leu)

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.413C>T (p.Ser138Leu)
HGVS:
  • NC_000001.11:g.40091349G>A
  • NG_009192.1:g.11122C>T
  • NM_000310.4:c.413C>TMANE SELECT
  • NM_001142604.2:c.125-1837C>T
  • NM_001363695.2:c.413C>T
  • NP_000301.1:p.Ser138Leu
  • NP_000301.1:p.Ser138Leu
  • NP_001350624.1:p.Ser138Leu
  • LRG_690t1:c.413C>T
  • LRG_690:g.11122C>T
  • LRG_690p1:p.Ser138Leu
  • NC_000001.10:g.40557021G>A
  • NM_000310.3:c.413C>T
  • P50897:p.Ser138Leu
Protein change:
S138L
Links:
UniProtKB: P50897#VAR_066875; dbSNP: rs386833646
NCBI 1000 Genomes Browser:
rs386833646
Molecular consequence:
  • NM_001142604.2:c.125-1837C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000310.4:c.413C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363695.2:c.413C>T - 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
SCV000082012Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
no assertion criteria provided
probable-pathogenicnot providednot provided

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

SCV000800709Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Uncertain significance
(May 18, 2018)
unknownclinical testing

Citation Link,

SCV001208999Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 18, 2023)
germlineclinical testing

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

SCV002085995Natera, Inc.
no assertion criteria provided
Uncertain significance
(Feb 5, 2020)
germlineclinical testing

SCV002518902Mendelics
criteria provided, single submitter

(Mendelics Assertion Criteria 2019)
Pathogenic
(May 4, 2022)
germlineclinical testing

Citation Link,

SCV0025730943billion
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Sep 1, 2022)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004204136Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 24, 2024)
unknownclinical 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

SCV000082012

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot provided1not providedliterature only
not providedgermlineyes1not providednot provided1not providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.

Iwama K, Mizuguchi T, Takeshita E, Nakagawa E, Okazaki T, Nomura Y, Iijima Y, Kajiura I, Sugai K, Saito T, Sasaki M, Yuge K, Saikusa T, Okamoto N, Takahashi S, Amamoto M, Tomita I, Kumada S, Anzai Y, Hoshino K, Fattal-Valevski A, Shiroma N, et al.

J Med Genet. 2019 Jun;56(6):396-407. doi: 10.1136/jmedgenet-2018-105775. Epub 2019 Mar 6.

PubMed [citation]
PMID:
30842224

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (4)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082012.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot provided PubMed (1)

Description

Converted during submission to Likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot provided1not providednot providednot providednot providednot providednot provided

From Counsyl, SCV000800709.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001208999.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 138 of the PPT1 protein (p.Ser138Leu). This variant is present in population databases (rs386833646, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis 1 (PMID: 21990111, 30842224; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56194). 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%. For these reasons, this variant has been classified as Pathogenic.

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

From Natera, Inc., SCV002085995.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV002518902.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From 3billion, SCV002573094.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). The variant is in trans with the other variant (NM_000310.4:c.433+1G>A). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.29). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PPT1-related disorder (PMID: 21990111). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Baylor Genetics, SCV004204136.2

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

Last Updated: Jun 17, 2024