ClinVar Miner

Submissions for variant NM_004937.3(CTNS):c.922G>A (p.Gly308Arg) (rs746307931)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000691400 SCV000819177 pathogenic Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis 2019-08-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 308 of the CTNS protein (p.Gly308Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs746307931, ExAC 0.002%). This variant has been reported as homozygous or in combination with other CTNS variants in several individuals affected with cystinosis (PMID: 9792862, 12204010, 15128704, 19863563, 26266097). ClinVar contains an entry for this variant (Variation ID: 267310). Experimental studies have shown that this missense change abolishes cystine transport activity in vitro (PMID: 11689434, 12204010). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000691400 SCV001163423 pathogenic Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000258031 SCV001337864 pathogenic Cystinosis 2020-01-30 criteria provided, single submitter clinical testing Variant summary: CTNS c.922G>A (p.Gly308Arg) results in a non-conservative amino acid change located in the sixth transmembrane domain (Kalatzis_2004) of 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-06 in 251050 control chromosomes (gnomAD). c.922G>A has been reported in the literature in multiple individuals affected with Cystinosis (Shotelersuk_1998, Attard_1999). These data indicate that the variant is very likely to be associated with disease. At least two functional studies reports this variant is sufficient to abolish the transport activity of cystinosin without altering its subcellular localization. Two Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000258031 SCV000328212 pathogenic Cystinosis 2016-10-06 no assertion criteria provided literature only
Natera, Inc. RCV000258031 SCV001463154 pathogenic Cystinosis 2020-09-16 no assertion criteria provided clinical testing

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