ClinVar Miner

Submissions for variant NM_004937.3(CTNS):c.839A>G (p.Lys280Arg)

dbSNP: rs2150925451
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002550250 SCV001576192 pathogenic Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases 2022-08-16 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1067346). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects CTNS function (PMID: 15128704, 28465352). 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 disruptive. This missense change has been observed in individual(s) with cystinosis (PMID: 10444339, 18178779; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 280 of the CTNS protein (p.Lys280Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002242880 SCV002511701 likely pathogenic Cystinosis 2023-09-12 criteria provided, single submitter clinical testing Variant summary: CTNS c.839A>G (p.Lys280Arg) results in a conservative amino acid change located in the fifth inter transmembrane domain (Kalatziz_2004) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250982 control chromosomes (gnomAD). c.839A>G has been reported in the literature in at least two individuals affected with juvenile/intermmediate Cystinosis, including one case where it was found in the compound heterozygous state in trans with a pathogenic variant (e.g. Theone_1999, Kalatzis_2004, Servais_2008). These data do not allow any strong conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Kalatzis_2004). The most pronounced variant effect results in abolishment (<1%) of normal Cystine transport activity. The following publications have been ascertained in the context of this evaluation (PMID: 15128704, 18178779, 10444339). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014, citing an internal observation of the variant in at least one individual, and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV003469636 SCV004215216 likely pathogenic Nephropathic cystinosis 2023-02-05 criteria provided, single submitter clinical testing

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