rs386833655

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000310.4(PPT1):​c.550G>A​(p.Glu184Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

7
8
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.69
Variant links:
Genes affected
PPT1 (HGNC:9325): (palmitoyl-protein thioesterase 1) The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a helix (size 4) in uniprot entity PPT1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000310.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.955
PP5
Variant 1-40080474-C-T is Pathogenic according to our data. Variant chr1-40080474-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40080474-C-T is described in Lovd as [Pathogenic]. Variant chr1-40080474-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PPT1NM_000310.4 linkuse as main transcriptc.550G>A p.Glu184Lys missense_variant 6/9 ENST00000642050.2 NP_000301.1
PPT1NM_001363695.2 linkuse as main transcriptc.550G>A p.Glu184Lys missense_variant 6/8 NP_001350624.1
PPT1NM_001142604.2 linkuse as main transcriptc.241G>A p.Glu81Lys missense_variant 3/6 NP_001136076.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PPT1ENST00000642050.2 linkuse as main transcriptc.550G>A p.Glu184Lys missense_variant 6/9 NM_000310.4 ENSP00000493153 P1P50897-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151930
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251404
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461644
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727130
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151930
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74190
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:4
Likely pathogenic, no assertion criteria providedliterature onlyJuha Muilu Group; Institute for Molecular Medicine Finland (FIMM)-- -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylAug 03, 2016- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsAug 29, 2023- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2024This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 184 of the PPT1 protein (p.Glu184Lys). This variant is present in population databases (rs386833655, gnomAD 0.01%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 10679943, 17044973). 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: 56204). 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. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 24, 2023Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 11440996); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24997880, 17044973, 9793631, 10679943, 34380004, 21990111, 9664077, 10781062, 11440996) -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 02, 2018- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 02, 2016The p.E184K pathogenic mutation (also known as c.550G>A), located in coding exon 6 of the PPT1 gene, results from a G to A substitution at nucleotide position 550. The glutamic acid at codon 184 is replaced by lysine, an amino acid with similar properties. This pathogenic mutation has been reported with a known pathogenic mutation and in the homozygous state in individuals with infantile neuronal ceroid lipofuscinoses (NCL) (Das AK et al. J Clin Invest. 1998; 102(2):361-70; Salonen T et al. Hum Mutat. 2000; 15(3):273-9). Functional studies in patient cells and in vitro studies found cells with this mutation had no detectable enzyme activity (Das AK et al. Hum Mol Genet. 2001; 10(13):1431-9). In addition, based on structural analysis, this mutation is expected to cause a conformational change in the palmitate-binding (Bellizzi JJ et al. Proc Natl Acad Sci USA. 2000; 97(9):4573-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 13, 2023Variant summary: PPT1 c.550G>A (p.Glu184Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251404 control chromosomes (gnomAD). c.550G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (examples: Das_1998, Salonen_2000, and Bi_2006). 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 function. The most pronounced variant effect results in <10% of normal activity (example: Das_2001). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;.;.;.;.;.;.
Eigen
Benign
-0.031
Eigen_PC
Benign
-0.038
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.34
D
MutationAssessor
Uncertain
2.5
M;.;.;.;.;.;.
MutationTaster
Benign
0.97
D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-1.7
.;.;.;.;.;N;.
REVEL
Pathogenic
0.73
Sift
Uncertain
0.029
.;.;.;.;.;D;.
Sift4G
Uncertain
0.027
.;.;.;.;.;D;.
Polyphen
0.81
P;.;.;.;.;D;.
Vest4
0.74
MutPred
0.88
Gain of ubiquitination at E184 (P = 0.0185);.;.;Gain of ubiquitination at E184 (P = 0.0185);Gain of ubiquitination at E184 (P = 0.0185);.;.;
MVP
0.96
MPC
0.44
ClinPred
0.67
D
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.93
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386833655; hg19: chr1-40546146; COSMIC: COSV65655081; COSMIC: COSV65655081; API