rs113994206
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_004937.3(CTNS):āc.473T>Cā(p.Leu158Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,598,042 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 (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L158L) has been classified as Likely benign.
Frequency
Consequence
NM_004937.3 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 |
---|---|---|---|---|---|---|---|
CTNS | NM_004937.3 | c.473T>C | p.Leu158Pro | missense_variant | 8/12 | ENST00000046640.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTNS | ENST00000046640.9 | c.473T>C | p.Leu158Pro | missense_variant | 8/12 | 1 | NM_004937.3 | P1 | |
CTNS-AS1 | ENST00000575741.1 | n.532+358A>G | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000435 AC: 6AN: 137842Hom.: 0 Cov.: 19
GnomAD3 exomes AF: 0.0000404 AC: 10AN: 247434Hom.: 0 AF XY: 0.0000298 AC XY: 4AN XY: 134102
GnomAD4 exome AF: 0.000118 AC: 172AN: 1460082Hom.: 0 Cov.: 32 AF XY: 0.0000978 AC XY: 71AN XY: 726218
GnomAD4 genome ? AF: 0.0000435 AC: 6AN: 137960Hom.: 0 Cov.: 19 AF XY: 0.0000452 AC XY: 3AN XY: 66398
ClinVar
Submissions by phenotype
Nephropathic cystinosis Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 25, 2023 | PS3, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2021 | Functional studies demonstrated that L158P allowed normal trafficking to the lysosomes, but that it abolished cystine transport (Kalatzis et al., 2004); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 10482956, 21963264, 28238446, 12644911, 28649545, 34237326, 32198276, 15128704) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 08, 2023 | - - |
Cystinosis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 13, 2022 | Variant summary: CTNS c.473T>C (p.Leu158Pro) results in a non-conservative amino acid change in 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 4e-05 in 247434 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CTNS causing Cystinosis (4e-05 vs 0.0025), allowing no conclusion about variant significance. c.473T>C has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Cystinosis (example, McGowan-Jordan_1999, Kalatzis_2004, Zykovich_2015, Ghazi_2017). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishment of cystine transport while not affecting the lysosomal localization of cystinosin (Kalatzis_2004). Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Juvenile nephropathic cystinosis;C2931013:Ocular cystinosis;C2931187:Nephropathic cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 22, 2021 | - - |
Juvenile nephropathic cystinosis;C0950123:Inborn genetic diseases;C2931013:Ocular cystinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 158 of the CTNS protein (p.Leu158Pro). This variant is present in population databases (rs113994206, gnomAD 0.008%). This missense change has been observed in individual(s) with cystinosis (PMID: 10482956, 28649545; Invitae). 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: 21439). 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 CTNS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTNS function (PMID: 15128704). 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