rs137852696

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_000310.4(PPT1):c.223A>C(p.Thr75Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000628 in 1,608,864 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T75T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 4.68

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000310.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

PP5

Variant 1-40092409-T-G is Pathogenic according to our data. Variant chr1-40092409-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 8900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40092409-T-G is described in Lovd as [Pathogenic]. Variant chr1-40092409-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PPT1	NM_000310.4 linkuse as main transcript	c.223A>C	p.Thr75Pro	missense_variant	2/9	ENST00000642050.2
PPT1	NM_001363695.2 linkuse as main transcript	c.223A>C	p.Thr75Pro	missense_variant	2/8
PPT1	NM_001142604.2 linkuse as main transcript	c.125-2897A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPT1	ENST00000642050.2 linkuse as main transcript	c.223A>C	p.Thr75Pro	missense_variant	2/9		NM_000310.4	P1	P50897-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251446

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135896

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000638

AC:

AN:

1456728

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

725080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.0000777

Gnomad4 OTH exome

AF:

0.0000996

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000852

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 09, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2018	Variant summary: PPT1 c.223A>C (p.Thr75Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 246324 control chromosomes (gnomAD).The variant, c.223A>C, has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease), including at least one homozygote (Mitchison_1998). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 75 of the PPT1 protein (p.Thr75Pro). This variant is present in population databases (rs137852696, gnomAD 0.007%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis 1 (PMID: 9425237, 26510000, 28559085). 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: 8900). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PPT1 function (PMID: 23539563). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000310.3(PPT1):c.223A>C(T75P) is classified as pathogenic in the context of PPT1-related neuronal ceroid lipofuscinosis and is associated with the juvenile form of this disease. Sources cited for classification include the following: PMID 9425237, 9664077 and 23539563. Classification of NM_000310.3(PPT1):c.223A>C(T75P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 20, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2021	Published functional studies demonstrate the variant results in reduced PPT1 enzyme activity (Miller et al., 2013); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14997939, 10649502, 26510000, 11520175, 19793631, 16720047, 22778232, 23542453, 11073228, 10781062, 16759889, 9664077, 20346914, 23857568, 29655203, 28559085, 23539563, 9425237) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 07, 2021	DNA sequence analysis of the PPT1 gene demonstrated a sequence change, c.223A>C, in exon 2 that results in an amino acid change, p.Thr75Pro. This sequence change has been described in the gnomAD database with a low frequency of 0.006% in African/African American subpopulation (dbSNP rs137852696). This sequence change has previously been described in the homozygous and compound heterozygous states in individuals and families with PPT1-related disorders (PMIDs: 9425237, 26510000). The p.Thr75Pro change affects a poorly conserved amino acid residue of the PPT1 protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr75Pro substitution. Functional studies suggest p.Thr75Pro reduces PPT1 enzyme activity (PMID: 23539563). Collectively these evidences suggest this p.Thr75Pro variant is pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2022

The c.223A>C (p.T75P) alteration is located in exon 2 (coding exon 2) of the PPT1 gene. This alteration results from a A to C substitution at nucleotide position 223, causing the threonine (T) at amino acid position 75 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (4/251446) total alleles studied. The highest observed frequency was 0.01% (1/16256) of African alleles. This mutation has been identified in multiple individuals in the compound heterozygous and homozygous state (Miller, 2013; Mitchison, 1998; Metelitsina, 2016; Das, 1998; Stone, 2017; Jilani, 2019). This amino acid position is not well conserved in available vertebrate species. This alteration has been shown to reduce PPT1 enzyme activity (Miller, 2013). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

PPT1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2023

The PPT1 c.223A>C variant is predicted to result in the amino acid substitution p.Thr75Pro. This variant has been documented in the homozygous and compound heterozygous states as causative for neuronal ceroid lipofuscinosis 1 (CLN1) in several affected patients (Mitchison et al.1998. PubMed ID: 9425237; Das et al. 1998. PubMed ID: 9664077). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-40558081-T-G). This variant is interpreted as pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Thr75Pro variant in PPT1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S, PS3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.18

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Benign

2.0

M;.;.;.;.;.

MutationTaster

Benign

0.092

A;A

PrimateAI

Benign

0.38

Polyphen

0.40

B;.;.;.;.;.

MVP

0.97

MPC

0.32

ClinPred

0.40

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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