rs119455954
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
Consequence
NM_000391.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.1094G>A | p.Cys365Tyr | missense_variant | 9/13 | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.1094G>A | p.Cys365Tyr | missense_variant | 9/13 | 1 | NM_000391.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251456Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135902
GnomAD4 exome AF: 0.0000910 AC: 133AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.0000798 AC XY: 58AN XY: 727240
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | 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). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Neuronal ceroid lipofuscinosis 2 Pathogenic:3Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 19, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | 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. - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 26, 2014 | - - |
Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 27, 2022 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 30, 2016 | 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." - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at