rs386833655

Positions:

chr1-40080474-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E184V) has been classified 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

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]

PPT1 links:

PPT1 (HGNC:):

PPT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000310.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-40080473-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1527936.Status of the report is criteria_provided_single_submitter, 1 stars.

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
PPT1	NM_000310.4 linkuse as main transcript	c.550G>A	p.Glu184Lys	missense_variant	6/9	ENST00000642050.2	NP_000301.1	P50897-1
PPT1	NM_001363695.2 linkuse as main transcript	c.550G>A	p.Glu184Lys	missense_variant	6/8		NP_001350624.1
PPT1	NM_001142604.2 linkuse as main transcript	c.241G>A	p.Glu81Lys	missense_variant	3/6		NP_001136076.1	P50897-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2 linkuse as main transcript	c.550G>A	p.Glu184Lys	missense_variant	6/9		NM_000310.4	ENSP00000493153.1		P50897-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151930

Hom.:

Cov.:

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:

AN:

251404

Hom.:

AF XY:

0.0000147

AC XY:

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:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

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:

AN:

151930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

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 provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This 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 submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	Published 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) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2016

The 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 submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 13, 2023

Variant 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

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;.;.;.;.

Eigen

Benign

-0.031

Eigen_PC

Benign

-0.038

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

.;D;D;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Uncertain

2.5

M;.;.;.;.;.;.

PrimateAI

Uncertain

0.53

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over