1-40080483-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000310.4(PPT1):c.541G>C(p.Val181Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 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 the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V181M) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.81

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet, Myriad Women’s Health

PPT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 26 ACMG points.

PS1

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

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 Pathogenic. ClinVar VariationId is 188857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 1-40080483-C-G is Pathogenic according to our data. Variant chr1-40080483-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1072746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPT1	NM_000310.4 link	c.541G>C	p.Val181Leu	missense_variant	Exon 6 of 9	ENST00000642050.2	NP_000301.1	P50897-1
PPT1	NM_001363695.2 link	c.541G>C	p.Val181Leu	missense_variant	Exon 6 of 8		NP_001350624.1
PPT1	NM_001142604.2 link	c.232G>C	p.Val78Leu	missense_variant	Exon 3 of 6		NP_001136076.1	P50897-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2 link	c.541G>C	p.Val181Leu	missense_variant	Exon 6 of 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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111762

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151758

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41252

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1

Pathogenic:2

Nov 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 02, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

May 03, 2021

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

(source)

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;.;.;.;.;.;.

PhyloP100

7.8

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

0.95

GERP RS

4.8

Varity_R

0.87

gMVP

0.60

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over