11-6616056-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000391.4(TPP1):c.1094G>A(p.Cys365Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000867 in 1,614,082 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. C365R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 5.56

Variant links:

Genes affected

TPP1 (HGNC:2073): (tripeptidyl peptidase 1) This gene encodes a member of the sedolisin family of serine proteases. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates, and has weaker endopeptidase activity. It is synthesized as a catalytically-inactive enzyme which is activated and auto-proteolyzed upon acidification. Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis, which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome. [provided by RefSeq, Jul 2008]

TPP1 links:

ENSG00000285338 (HGNC:):

ENSG00000285338 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-6616057-A-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 11-6616056-C-T is Pathogenic according to our data. Variant chr11-6616056-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6616056-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4 link	c.1094G>A	p.Cys365Tyr	missense_variant	Exon 9 of 13	ENST00000299427.12	NP_000382.3	O14773-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12 link	c.1094G>A	p.Cys365Tyr	missense_variant	Exon 9 of 13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

251456

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000910

AC:

133

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727240

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:

0.000112

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

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:

0.0000481

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 365 of the TPP1 protein (p.Cys365Tyr). This variant is present in population databases (rs119455954, gnomAD 0.004%). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis (PMID: 9788728, 10330339, 26075876). This variant is also known as c.4655G>A and c.1107T>C. ClinVar contains an entry for this variant (Variation ID: 2642). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TPP1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies have shown a decrease in TPP1 protease activity in the fibroblasts of affected patients (Sleat et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25326635, 19038966, 19038967, 10330339, 21990111, 19246452, 9788728, 29655203, 32146219, 32329550, 31283065, 31589614, 33268510, 26822727, 23042927, 26075876, 30771299, 9295267) -

Nov 18, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis 2

Pathogenic:3Other:1

Jun 26, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 19, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found twice in our laboratory in trans with another pathogenic variant: with W366X in a 7-year-old male with developmental delay/regression, hypertonia/spasticity, seizure, ataxia, myoclonus, progressive brain atrophy, vision loss; with c.509-1G>C in a 5-year-old male with developmental regression, truncal ataxia, seizure disorder, optic atrophy, diffuse brain atrophy. Heterozygotes are expected to be asymptomatic carriers. -

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2

Pathogenic:1

May 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Dec 30, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The TPP1 c.1094G>A (p.Cys365Tyr) variant located in the Peptidase S8/S53 domain (via InterPro) causes a missense change involving the alteration of a Cysteine, which has been implicated to play a key role in disulfide linkages needed to stabilize the fold (Guhaniyogi_2009 (PMID: 19038967). In addition, 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121330 (1/60665), which does not exceed the estimated maximal expected allele frequency for a pathogenic TPP1 variant of 1/338. Multiple publications cite individuals affected with Late-Infantile Neuronal Ceroid-Lipofuscinoses, who are homozygous or compound heterozygous for the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic" or "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic." -

TPP1-related disorder

Pathogenic:1

May 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TPP1 c.1094G>A variant is predicted to result in the amino acid substitution p.Cys365Tyr. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with neuronal ceroid lipofuscinosis (Table 1, Sleat et al. 1999. PubMed ID: 10330339; Table 1, Di Fruscio et al. 2015. PubMed ID: 26075876). This variant is reported in 0.0039% of alleles in individuals of European (non-Finnish) descent in gnomAD. An alternate nucleotide substitution affecting the same amino acid (p.Cys365Arg) has been reported in an individual with neuronal ceroid lipofuscinosis (Table 1, Sleat et al. 1999. PubMed ID: 10330339). In summary, the c.1094G>A (p.Cys365Tyr) variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

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

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.96

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;.;.;.;.;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-9.0

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

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0040

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

Polyphen

1.0

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

Vest4

0.94

MVP

1.0

MPC

0.99

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.98

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