Submissions for variant NM_004937.3(CTNS):c.559_561+24del

dbSNP: rs113994211

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000020627	SCV000221139	likely pathogenic	Nephropathic cystinosis	2015-02-15	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513143	SCV000816935	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2024-08-28	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 8 of the CTNS gene. RNA analysis indicates that a similar copy number variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs771633120, gnomAD 0.008%). A similar copy number variant has been observed in individual(s) with infantile cystinosis (PMID: 11562417). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 898–900_x0001_+24del27 . ClinVar contains an entry for this variant (Variation ID: 21442). Studies have shown that a similar copy number variant results in multiple aberrant spliced transcripts, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11562417). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	RCV001843459	SCV002102789	likely pathogenic	Infantile nephropathic cystinosis	2022-03-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005089290	SCV002808694	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis	2022-03-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000020627	SCV004212931	pathogenic	Nephropathic cystinosis	2024-02-05	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020627	SCV000041139	pathologic	Nephropathic cystinosis	2011-08-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328195	SCV001449313	pathogenic	Cystinosis	2018-03-12	no assertion criteria provided	clinical testing	This individual is heterozygous for the c.559_561+24del variant in the CTNS gene. This variant has been previously reported multiple times, as 898-900_24del27, in the literature as a known founder mutation, originating in Brittany, France. This deletion has been shown to abolish the splice donor consensus site of CTNS exon 8, resulting in aberrant transcript splicing (Kalatzis et al J Am Soc Nephrol 2001 (12):2170-2174; Attard et al Hum Mol Genetics 1999 8(13):2507-2514). This variant is considered to be pathogenic according to the ACMG guidelines.
PreventionGenetics, part of Exact Sciences	RCV004748536	SCV005362051	pathogenic	CTNS-related disorder	2024-06-07	no assertion criteria provided	clinical testing	The CTNS c.559_561+24del27 variant is predicted to result in a deletion affecting a canonical splice site. This variant is predicted to result in deletion of the last three nucleotides of exon 8 as well as the first twenty-four nucleotides of intron 8. This deletion encompasses the canonical splice donor site at the exon 8/intron 8 junction and is predicted to impact splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with ocular or nephropathic cystinosis (Table 1, Attard et al. 1999. PubMed ID: 10556299; Browning et al. 2019. PubMed ID: 30957593; Table 2, Marik et al. 2022. PubMed ID: 35738466). This variant is reported in 0.0078% of alleles in individuals of European (non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in CTNS are expected to be pathogenic. This variant is interpreted as pathogenic.