rs119455953
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
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.1093T>C | p.Cys365Arg | missense_variant | 9/13 | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.1093T>C | p.Cys365Arg | missense_variant | 9/13 | 1 | NM_000391.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 2 Pathogenic:1Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 19, 1997 | - - |
TPP1-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 30, 2023 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at