ClinVar Miner

Submissions for variant NM_004937.3(CTNS):c.422C>T (p.Ser141Phe) (rs1436441738)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000807325 SCV000947372 pathogenic Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis 2019-04-15 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 141 of the CTNS protein (p.Ser141Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another CTNS variant in individuals affected with cystinosis, and has been shown to segregate with disease in a family (PMID: 15128704, 19852576, 25326109). Experimental studies have shown that this missense change abolishes cystine transport activity (PMID: 15128704, 29467429). For these reasons, this variant has been classified as Pathogenic.
Diagnostics Lab (ASPIRE), CSIR - Centre for Cellular and Molecular Biology RCV000807325 SCV000999249 likely pathogenic Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis 2019-10-10 criteria provided, single submitter clinical testing The Ser141Phe variant is not present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC) however present in Genome Aggregation Database (gnomAD), dbSNP (rs1436441738) and our in-house exome database in heterozygous state at a very low frequency (MAF<0.0006). The variant was reported earlier to Human Genome Mutation Database (CM041752) in other similarly affected individuals [Kalatzis et al., Hum Mol Genet 2004]. In-silico pathogenicity prediction programs like SIFT, Polyphen2, Mutation Taster2, CADD etc. predicted this variant as likely disease causing. As per ACMG guidelines the variant has been classified as likely pathogenic.

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