chr1-40080483-C-A

Position:

chr1-40080483-C-A

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000310.4(PPT1):c.541G>T(p.Val181Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,306 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V181M) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.81

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 26 ACMG points.

PS1

Transcript NM_000310.4 (PPT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1072746

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 chr1-40080483-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 1-40080483-C-A is Pathogenic according to our data. Variant chr1-40080483-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40080483-C-A is described in Lovd as [Pathogenic]. Variant chr1-40080483-C-A 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.541G>T	p.Val181Leu	missense_variant	6/9	ENST00000642050.2	NP_000301.1	P50897-1
PPT1	NM_001363695.2 linkuse as main transcript	c.541G>T	p.Val181Leu	missense_variant	6/8		NP_001350624.1
PPT1	NM_001142604.2 linkuse as main transcript	c.232G>T	p.Val78Leu	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.541G>T	p.Val181Leu	missense_variant	6/9		NM_000310.4	ENSP00000493153.1		P50897-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000119

AC:

AN:

251372

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151758

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74072

show subpopulations

Gnomad4 AFR

AF:

0.00

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

ExAC

AF:

0.0000165

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	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 present in population databases (rs148412181, gnomAD 0.007%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (NCL) (PMID: 10477428, 19302939, 21499717). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56202). 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%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 28878621). 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: 9664077, 11440996, 22387303, 23374165, 28878621). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 09, 2015	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2023	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: 12125808, 21499717, 19302939, 21990111, 15965709, 28878621, 34426522, 31741823, 34440436, 10477428, 22387303, 12796825) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 06, 2023	PP3, PP4, PM2_moderate, PM3_strong, PM5, PS4_moderate -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Apr 12, 2022

ACMG categories: PS3,PS4,PM2,PP3,PP5 -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 31, 2021

Variant summary: PPT1 c.541G>T (p.Val181Leu) 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 1.2e-05 in 251372 control chromosomes. c.541G>T has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Simonati_2009, Perez-Poyato_2011, Pezzini_2017, Jiliani_2019). 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 PPT1 enzyme activity (example, Perez-Poyato_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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

0.83

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

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

Eigen

Benign

0.16

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

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

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.5

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

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.4

.;.;.;.;.;N;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.015

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

Sift4G

Uncertain

0.023

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

Polyphen

0.098

B;.;.;.;.;P;.

Vest4

0.72

MutPred

0.93

Loss of sheet (P = 0.0315);.;.;Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;

MVP

0.95

MPC

0.25

ClinPred

0.85

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.60

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