11-6616057-A-G

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.1093T>C(p.Cys365Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,070 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. C365Y) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 6.57

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 chr11-6616056-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 11-6616057-A-G is Pathogenic according to our data. Variant chr11-6616057-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6616057-A-G is described in Lovd as [Likely_pathogenic]. Variant chr11-6616057-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4 link	c.1093T>C	p.Cys365Arg	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.1093T>C	p.Cys365Arg	missense_variant	Exon 9 of 13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

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:

1461876

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

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

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2

Pathogenic:1Other:1

Sep 19, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Jan 16, 2024

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 arginine, which is basic and polar, at codon 365 of the TPP1 protein (p.Cys365Arg). This variant is present in population databases (rs119455953, gnomAD 0.007%). This missense change has been observed in individual(s) with TPP1-related conditions (PMID: 10330339). This variant is also known as 4654T>C. ClinVar contains an entry for this variant (Variation ID: 2641). 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 TPP1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TPP1 function (PMID: 20340139). This variant disrupts the p.Cys365 amino acid residue in TPP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9788728, 10330339, 26075876). 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. -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Mar 12, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TPP1 c.1093T>C (p.Cys365Arg) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Another missense variant altering this residue (p.Cys365Tyr) has been classified as pathogenic. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes (gnomAD). c.1093T>C has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) or epilepsy (e.g. Sleat_1999, Lindy_2018, Nickel_2018, Haviland_2023). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in the complete loss of enzymatic activity (Walus_2010). The following publications have been ascertained in the context of this evaluation (PMID: 10330339, 20340139, 29655203, 36403551, 30119717). ClinVar contains an entry for this variant (Variation ID: 2641). Based on the evidence outlined above, the variant was classified as pathogenic. -

TPP1-related disorder

Pathogenic:1

Jul 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TPP1 c.1093T>C variant is predicted to result in the amino acid substitution p.Cys365Arg. This variant has been reported in individuals with TPP1-related autosomal recessive disorders, and functional studies support its pathogenicity (Sleat et al. 1997. PubMed ID: 9295267; Walus et al. 2010. PubMed ID: 20340139; Lindy et al. 2018. PubMed ID: 29655203; Sleat et al. 1999. PubMed ID: 10330339). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-6637288-A-G). An alternate missense variant at the same amino acid position has been reported as causative (p.Cys365Tyr; Sleat et al. 1999. PubMed ID: 10330339). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

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

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

D;.;D;.;T;.;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

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

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-8.1

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

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0060

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

Polyphen

1.0

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

Vest4

0.96

MutPred

0.91

Gain of MoRF binding (P = 0.0043);.;.;.;.;.;.;

MVP

1.0

MPC

1.0

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.99

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