rs121908195

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000391.4(TPP1):c.229G>C(p.Gly77Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

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

Conservation

PhyloP100: 3.73

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-6618776-C-G is Pathogenic according to our data. Variant chr11-6618776-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6618776-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPP1	NM_000391.4 linkuse as main transcript	c.229G>C	p.Gly77Arg	missense_variant, splice_region_variant	3/13	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12 linkuse as main transcript	c.229G>C	p.Gly77Arg	missense_variant, splice_region_variant	3/13	1	NM_000391.4	ENSP00000299427	P1	O14773-1
	ENST00000545572.1 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250960

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135672

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:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461454

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727034

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

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2023	Experimental studies have shown that this missense change affects TPP1 function (PMID: 18411270, 20340139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 207567). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 10330339, 30119717, 30771299, 31741823). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 77 of the TPP1 protein (p.Gly77Arg). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2012	p.Gly77Arg (GGA>CGA): c.229 G>C in exon 3 in the TPP1 gene (NM_000391.3) has been reported previously in association with late-infantile neuronal ceroid lipofuscinosis (LINCL) (Sleat et al., 1999). The Gly77Arg mutation alters a highly conserved position in the pro-segment of the TPP1 protein, and in vitro functional studies indicate that this mutation impairs protein folding and significantly reduces TPP1 enzyme activity (Walus et al., 2010). We interpret G77R as a disease-causing mutation. The variant is found in EPILEPSY panel(s). -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 27, 2021

Variant summary: TPP1 c.229G>C (p.Gly77Arg) results in a non-conservative amino acid change located in the activation domain (IPR015366) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, the variant is located to the last nucleotide of exon 3, therefore it can also affect splicing. Computational tools predict a significant impact on normal splicing: 2 predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250960 control chromosomes (gnomAD). The variant, c.229G>C, has been reported in the literature, in compound heterozygous- and homozygous state, in at least three individuals who were affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Retterer_2015, Nickel_2018, Jilani_2019, Lukacs_2019, Dozieres-Puyravel_2020, Estublier_2020, Kovacs_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating the protein level effect of the variant (i.e. expressing it from an intronless cDNA construct), and demonstrated very low residual enzyme activity and altered intracellular trafficking in a mammalian cell system (Walus_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Neuronal ceroid lipofuscinosis 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

D;D;T

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.0

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.0

D;.;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.0030

D;.;.

Polyphen

1.0

D;.;.

Vest4

0.84

MutPred

0.97

Loss of ubiquitination at K78 (P = 0.0566);Loss of ubiquitination at K78 (P = 0.0566);Loss of ubiquitination at K78 (P = 0.0566);

MVP

0.92

MPC

0.82

ClinPred

1.0

GERP RS

5.0

Varity_R

0.91

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.80

Position offset: 0

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