NM_004937.3(CTNS):c.1015G>A (p.Gly339Arg) AND Cystinosis

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 2, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001193377.11

Allele description [Variation Report for NM_004937.3(CTNS):c.1015G>A (p.Gly339Arg)]

NM_004937.3(CTNS):c.1015G>A (p.Gly339Arg)

Gene:

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.1015G>A (p.Gly339Arg)

HGVS:

NC_000017.11:g.3660280G>A
NG_012489.2:g.28813G>A
NM_001031681.3:c.1015G>A
NM_001374492.1:c.1015G>A
NM_001374493.1:c.574G>A
NM_001374494.1:c.574G>A
NM_001374495.1:c.574G>A
NM_001374496.1:c.574G>A
NM_004937.3:c.1015G>AMANE SELECT
NP_001026851.2:p.Gly339Arg
NP_001361421.1:p.Gly339Arg
NP_001361422.1:p.Gly192Arg
NP_001361423.1:p.Gly192Arg
NP_001361424.1:p.Gly192Arg
NP_001361425.1:p.Gly192Arg
NP_004928.2:p.Gly339Arg
NC_000017.10:g.3563574G>A
NM_001031681.2:c.1015G>A
NM_004937.2:c.1015G>A
O60931:p.Gly339Arg

Protein change:

G192R; GLY339ARG

Links:

UniProtKB: O60931#VAR_010695; OMIM: 606272.0015; dbSNP: rs121908127

NCBI 1000 Genomes Browser:

rs121908127

Molecular consequence:

NM_001031681.3:c.1015G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374492.1:c.1015G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374493.1:c.574G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374494.1:c.574G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374495.1:c.574G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374496.1:c.574G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004937.3:c.1015G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystinosis
Synonyms:: Cystine diathesis; Cystine disease; Cystine storage disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0016239; MedGen: C4316899

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001362153	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 16, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12825071, 11565547 Citation Link,
SCV001463155	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004848898	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001362153

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 16, 2019)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001463155

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 16, 2020)

germline

clinical testing

SCV004848898

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 2, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Mutational spectrum of the CTNS gene in Italy.

Mason S, Pepe G, Dall'Amico R, Tartaglia S, Casciani S, Greco M, Bencivenga P, Murer L, Rizzoni G, Tenconi R, Clementi M.

Eur J Hum Genet. 2003 Jul;11(7):503-8.

PubMed [citation]

PMID:: 12825071

A G339R mutation in the CTNS gene is a common cause of nephropathic cystinosis in the south western Ontario Amish Mennonite population.

Rupar CA, Matsell D, Surry S, Siu V.

J Med Genet. 2001 Sep;38(9):615-6. No abstract available.

PubMed [citation]

PMID:: 11565547
PMCID:: PMC1734937

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362153.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: CTNS c.1015G>A (p.Gly339Arg) 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 3.2e-05 in 251256 control chromosomes (gnomAD). c.1015G>A has been reported in the literature in multiple compound heterozygote and homozygote individuals affected with Cystinosis (eg- Mason_2003, Rupar_2001). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was 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

From Natera, Inc., SCV001463155.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848898.1

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

Description

The p.Gly339Arg variant in CTNS has been reported in >10 individuals with cystinosis and segregated with disease in 2 families (Shotelersuk 1998 PMID: 9792862, Rupar 2001 PMID: 11565547, Kalatzis 2002 PMID: 12442267, Kalatzis 2004 PMID: 15128704, Savostyanov 2022 PMID: 35571017). It was also identified in 0.006% (4/68046) of European chromosomes by gnomAD, v.3 (http://gnomad.broadinstitute.org), and is reported in ClinVar (Variation ID 4455). In vitro funtional studies support an impact on protein function, and leukocyte cystine levels measured in patients were markedly increased (Shotelersuk 1998 PMID: 9792862, Kalatzis 2002 PMID: 12442267, Kalatzis 2004 PMID: 15128704). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystinosis. ACMG/AMP criteria applied: PM3_VeryStrong , PS3, PP1_Moderate, PP3, PP4, PM2_Supporting.

#	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: Jul 15, 2024

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