NM_000310.4(PPT1):c.541G>C (p.Val181Leu) AND Neuronal ceroid lipofuscinosis 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 2, 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:: RCV001385552.9

Allele description [Variation Report for NM_000310.4(PPT1):c.541G>C (p.Val181Leu)]

NM_000310.4(PPT1):c.541G>C (p.Val181Leu)

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>C (p.Val181Leu)

HGVS:

NC_000001.11:g.40080483C>G
NG_009192.1:g.21988G>C
NM_000310.4:c.541G>CMANE SELECT
NM_001142604.2:c.232G>C
NM_001363695.2:c.541G>C
NP_000301.1:p.Val181Leu
NP_001136076.1:p.Val78Leu
NP_001350624.1:p.Val181Leu
LRG_690t1:c.541G>C
LRG_690:g.21988G>C
NC_000001.10:g.40546155C>G
NM_000310.3:c.541G>C

Protein change:

V181L

Links:

dbSNP: rs148412181

NCBI 1000 Genomes Browser:

rs148412181

Molecular consequence:

NM_000310.4:c.541G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142604.2:c.232G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363695.2:c.541G>C - 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
SCV001585444	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 6, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10477428, 19302939, 21499717, 22387303, 23374165, 28492532
SCV005052445	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 2, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001585444

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 6, 2023)

germline

clinical testing

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

SCV005052445

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 2, 2024)

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	unknown	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 basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5.

Mole SE, Mitchison HM, Munroe PB.

Hum Mutat. 1999;14(3):199-215. Review.

PubMed [citation]

PMID:: 10477428

Variant late infantile neuronal ceroid lipofuscinosis because of CLN1 mutations.

Simonati A, Tessa A, Bernardina BD, Biancheri R, Veneselli E, Tozzi G, Bonsignore M, Grosso S, Piemonte F, Santorelli FM.

Pediatr Neurol. 2009 Apr;40(4):271-6. doi: 10.1016/j.pediatrneurol.2008.10.018.

PubMed [citation]

PMID:: 19302939

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001585444.5

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

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 181 of the PPT1 protein (p.Val181Leu). This variant is not present in population databases (gnomAD no frequency). A different variant (c.541G>T) giving rise to the same protein effect has been determined to be pathogenic (PMID: 10477428, 19302939, 21499717). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 1072746). 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 80%. 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: 22387303, 23374165). 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 Baylor Genetics, SCV005052445.1

#	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: Sep 29, 2024

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