Submissions for variant NM_004937.3(CTNS):c.970G>A (p.Asp324Asn)

gnomAD frequency: 0.00072  dbSNP: rs140326392

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000392314	SCV000402241	uncertain significance	Ocular cystinosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000310091	SCV000402242	uncertain significance	Nephropathic cystinosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV002522944	SCV000821542	uncertain significance	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 324 of the CTNS protein (p.Asp324Asn). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is present in population databases (rs140326392, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CTNS-related conditions. ClinVar contains an entry for this variant (Variation ID: 322844). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000693664	SCV002777255	uncertain significance	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis	2022-05-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002510860	SCV002822349	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001274186	SCV001458024	uncertain significance	Cystinosis	2019-11-11	no assertion criteria provided	clinical testing