NM_004937.3(CTNS):c.473T>C (p.Leu158Pro) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 11, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002513140.9

Allele description [Variation Report for NM_004937.3(CTNS):c.473T>C (p.Leu158Pro)]

NM_004937.3(CTNS):c.473T>C (p.Leu158Pro)

Genes:

CTNS-AS1:CTNS antisense RNA 1 [Gene - HGNC]
CTNS:cystinosin, lysosomal cystine transporter [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.2

Genomic location:

Preferred name:

NM_004937.3(CTNS):c.473T>C (p.Leu158Pro)

HGVS:

NC_000017.11:g.3656498T>C
NG_012489.2:g.25031T>C
NM_001031681.3:c.473T>C
NM_001374492.1:c.473T>C
NM_001374493.1:c.32T>C
NM_001374494.1:c.32T>C
NM_001374495.1:c.32T>C
NM_001374496.1:c.32T>C
NM_004937.3:c.473T>CMANE SELECT
NP_001026851.2:p.Leu158Pro
NP_001026851.2:p.Leu158Pro
NP_001361421.1:p.Leu158Pro
NP_001361422.1:p.Leu11Pro
NP_001361423.1:p.Leu11Pro
NP_001361424.1:p.Leu11Pro
NP_001361425.1:p.Leu11Pro
NP_004928.2:p.Leu158Pro
NC_000017.10:g.3559792T>C
NM_001031681.2:c.473T>C
NM_004937.2:c.473T>C
O60931:p.Leu158Pro

Protein change:

L11P

Links:

UniProtKB: O60931#VAR_010680; dbSNP: rs113994206

NCBI 1000 Genomes Browser:

rs113994206

Molecular consequence:

NM_001031681.3:c.473T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374492.1:c.473T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374493.1:c.32T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374494.1:c.32T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374495.1:c.32T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374496.1:c.32T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004937.3:c.473T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Ocular cystinosis
Synonyms:: Cystinosis, ocular nonnephropathic; Cystinosis, adult, nonnephropathic; Cystinosis, benign, nonnephropathic
Identifiers:: MONDO: MONDO:0009064; MedGen: C2931013; Orphanet: 213; OMIM: 219750

Name:: Juvenile nephropathic cystinosis
Synonyms:: CYSTINOSIS, LATE-ONSET JUVENILE OR ADOLESCENT NEPHROPATHIC TYPE
Identifiers:: MONDO: MONDO:0009066; MedGen: C0268626; Orphanet: 213; Orphanet: 411634; OMIM: 219900

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001205465	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10482956, 28649545, 15128704, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001205465

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation.

McGowan-Jordan J, Stoddard K, Podolsky L, Orrbine E, McLaine P, Town M, Goodyer P, MacKenzie A, Heick H.

Eur J Hum Genet. 1999 Sep;7(6):671-8.

PubMed [citation]

PMID:: 10482956

CTNS mutations in publicly-available human cystinosis cell lines.

Zykovich A, Kinkade R, Royal G, Zankel T.

Mol Genet Metab Rep. 2015 Dec;5:63-66. doi: 10.1016/j.ymgmr.2015.10.007.

PubMed [citation]

PMID:: 28649545
PMCID:: PMC5471396

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001205465.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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