11-6617045-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000391.4(TPP1):c.617G>A(p.Arg206His) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,006 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. R206C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1O:1

Conservation

PhyloP100: 4.78

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a helix (size 6) in uniprot entity TPP1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000391.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-6617046-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 11-6617045-C-T is Pathogenic according to our data. Variant chr11-6617045-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6617045-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.617G>A	p.Arg206His	missense_variant	Exon 6 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.617G>A	p.Arg206His	missense_variant	Exon 6 of 13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251206

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135784

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727234

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:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jul 29, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 206 of the TPP1 protein (p.Arg206His). This variant is present in population databases (rs121908209, gnomAD 0.0009%). This missense change has been observed in individual(s) with TPP1-related conditions (PMID: 12698559; internal data). 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: 68748). 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%. This variant disrupts the p.Arg206 amino acid residue in TPP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10665500, 20340139, 30541466). 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 2

Pathogenic:1Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 13, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.87 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068748 /PMID: 12698559 /3billion dataset). Different missense changes at the same codon (p.Arg206Cys, p.Arg206Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002646, VCV001068193 /PMID: 10477428, 35614200). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Aug 29, 2012

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Feb 28, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The p.R206H variant (also known as c.617G>A), located in coding exon 6 of the TPP1 gene, results from a G to A substitution at nucleotide position 617. The arginine at codon 206 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported in an individual with late infantile neuronal ceroid lipofuscinosis (CLN2); however, clinical details were limited (Kousi M. Hum. Mutat.. 2012 Jan;33(1):42-63). In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

T;T;T

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.2

D;.;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.016

D;.;.

Sift4G

Benign

0.19

T;.;.

Polyphen

1.0

D;.;.

Vest4

0.80

MutPred

0.88

Loss of MoRF binding (P = 0.0283);.;Loss of MoRF binding (P = 0.0283);

MVP

0.98

MPC

0.84

ClinPred

0.95

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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