17-3656498-T-C

Position:

chr17-3656498-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_004937.3(CTNS):c.473T>C(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 (★★).

Frequency

Genomes: 𝑓 0.000043 ( 0 hom., cov: 19)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CTNS
NM_004937.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 5.99

Variant links:

Genes affected

CTNS (HGNC:2518): (cystinosin, lysosomal cystine transporter) This gene encodes a seven-transmembrane domain protein that functions to transport cystine out of lysosomes. Its activity is driven by the H+ electrochemical gradient of the lysosomal membrane. Mutations in this gene cause cystinosis, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

CTNS links:

CTNS-AS1 (HGNC:56090): (CTNS antisense RNA 1)

CTNS-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain PQ-loop 1 (size 66) in uniprot entity CTNS_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004937.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 17-3656498-T-C is Pathogenic according to our data. Variant chr17-3656498-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3 linkuse as main transcript	c.473T>C	p.Leu158Pro	missense_variant	8/12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9 linkuse as main transcript	c.473T>C	p.Leu158Pro	missense_variant	8/12	1	NM_004937.3	ENSP00000046640	P1	O60931-1
CTNS-AS1	ENST00000575741.1 linkuse as main transcript	n.532+358A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000435

AC:

AN:

137842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000561

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000617

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000404

AC:

AN:

247434

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

134102

show subpopulations

Gnomad AFR exome

AF:

0.0000633

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:

0.0000716

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000118

AC:

172

AN:

1460082

Hom.:

Cov.:

AF XY:

0.0000978

AC XY:

AN XY:

726218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

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:

0.000144

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000435

AC:

AN:

137960

Hom.:

Cov.:

AF XY:

0.0000452

AC XY:

AN XY:

66398

show subpopulations

Gnomad4 AFR

AF:

0.0000559

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000617

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000742

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephropathic cystinosis

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 25, 2023	PS3, PM3 -
not provided, no classification provided	literature only	GeneReviews	-	- -

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	- -

CTNS-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2024

The CTNS c.473T>C variant is predicted to result in the amino acid substitution p.Leu158Pro. This variant has been reported to be causative for cystinosis (McGowan-Jordan et al. 1999. PubMed ID: 10482956; Kalatzis et al. 2004. PubMed ID: 15128704; Zykovich et al. 2015. PubMed ID: 28649545). We have also observed this variant internally, along with a second causative CTNS variant, in several different affected individuals. Of note, the p.Leu158 residue resides within the second transmembrane domain of the cystinosin protein. In a functional study, the transport activity of the cystinosin protein containing the p.Leu158Pro amino acid substitution was reduced to ~1% of wild-type cystinosin (Kalatzis et al. 2004. PubMed ID: 15128704). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

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

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

T;D;.;T;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

H;H;.;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.7

D;D;.;.;.

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;.;.;.

Sift4G

Pathogenic

0.0

D;D;.;D;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.98

MVP

0.99

MPC

0.87

ClinPred

1.0

GERP RS

4.8

Varity_R

0.97

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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