rs121908200

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000391.4(TPP1):​c.1266G>C​(p.Gln422His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000142 in 1,614,092 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense, splice_region

Scores

14
3
2
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 6.96
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.928
PP5
Variant 11-6615442-C-G is Pathogenic according to our data. Variant chr11-6615442-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 68738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6615442-C-G is described in Lovd as [Likely_pathogenic]. Variant chr11-6615442-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPP1NM_000391.4 linkc.1266G>C p.Gln422His missense_variant, splice_region_variant 10/13 ENST00000299427.12 NP_000382.3 O14773-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPP1ENST00000299427.12 linkc.1266G>C p.Gln422His missense_variant, splice_region_variant 10/131 NM_000391.4 ENSP00000299427.6 O14773-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251454
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
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:
0.0000137
AC:
20
AN:
1461890
Hom.:
0
Cov.:
34
AF XY:
0.0000124
AC XY:
9
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
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
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000227
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2 Pathogenic:2Other:1
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 18, 2017- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 24, 2020- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 11, 2022Published functional studies demonstrate a damaging effect by decreased or zero activity versus wild type (Steinfeld R et al., 2004; Walus M et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; 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: 25356970, 26795593, 20340139, 19038966, 10330339, 12376936, 29655203, 15317752, 22612257) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 20, 2023This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 422 of the TPP1 protein (p.Gln422His). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121908200, gnomAD 0.006%). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis (LINCL) (PMID: 10330339, 12376936, 22612257, 25356970). 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: 68738). 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. Experimental studies have shown that this missense change affects TPP1 function (PMID: 10330339). 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. -
Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 11, 2024- -
Autosomal recessive spinocerebellar ataxia 7 Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 26, 2013​B1) TPP1 c.1266G>C (p.Q422H)The c.1266G>C (p.Q422H) alteration is located in exon 10 of the TPP1 gene. This alteration results from a G to C substitution at nucleotide position 1266, resulting in an amino acid substitution of glutamine (Q) for histidine (H) at codon 422.<u>​The missense change is rare in healthy cohorts</u>:Based on data from the NHLBI Exome Sequencing Project (ESP), the TPP1 c.1266G>C (p.Q422H) alteration has an overall frequency of approximately 0.01% (1/10758 total alleles studied). The C-allele was observed in 0.01% (1/7020) of European American alleles and has not been observed (0%) in African Americans among of 3738 total alleles studied. The alteration has not been observed in the homozygous state out of 5379 individuals. Allele frequency data for alterations at this nucleotide position are not currently available from the 1000 Genomes Project.<u>The altered amino acid is conserved throughout evolution</u>:The Q422 amino acid is conserved throughout vertebrate evolution.<u>The alteration is predicted deleterious by in silico models:</u>The Q422H alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses.<u>The amino acid change has been observed in affected individuals:</u>This alteration is reported in the HGMD database (Accession# CM990373). This alteration is among the most common TPP1 mutations, accounting for ~7% of mutant alleles observed in affected individuals (Sleat, 1999).Based on the available evidence, the TPP1 c.1266G>C (p.Q422H) alteration is classified as a pathogenic mutation. -
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 27, 2020Variant summary: TPP1 c.1266G>C (p.Gln422His) results in a non-conservative amino acid change located in the Sedolisin domain (IPR030400) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251454 control chromosomes. c.1266G>C has been reported in the literature in multiple individuals from diverse ethnicities affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Sleat_1999). 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 abnormal processing, impaired trafficking and impaired secretion of TPPI with non detectable levels of TPPI activity in vitro (Walus_2010). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
36
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;.;.;.;.;.;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.82
T;.;T;.;D;.;T
M_CAP
Pathogenic
0.50
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.6
H;.;.;.;.;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-4.6
D;D;.;.;.;.;.
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0010
D;D;.;.;.;.;.
Sift4G
Pathogenic
0.0
D;D;.;.;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.
Vest4
0.96
MutPred
0.79
Loss of solvent accessibility (P = 0.0576);.;.;.;.;.;.;
MVP
0.97
MPC
0.73
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.88
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.77
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.77
Position offset: -29

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.

Other links and lift over

dbSNP: rs121908200; hg19: chr11-6636673; API